Pain, 41 (1990) 167-234 Elsevier
167
PAIN 01600
Basic Section Review A rtide
Visceral pain: a review
experimental studies
T.J. Ness a,b and G.F. Gebhart b Departments of a Anesthesia and b Pharmacology, College of Medicine, Unioersity of lowa, lowa City, 1,4 52242 (U.S.A.) (Accepted for publication: 15 January 1990)
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophysiological studies of visceral primary afferents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adequate visceral stimuli and nociceptive responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organization of the review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrical stimulatior as a noxious visceral stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical stimuli as noxious visceral stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischemia as a noxious visceral stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical stimuli as noxious visceral stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Final summary and comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
167 169 173 174 175 178 188 205 208 214 218 218
Summary This paper reviews clinical and basic science research reports and is directed toward an understanding of visceral pain, with emphasis on studies related to spinal processing. Four main types of visceral stimuli have been employed in experimental studies of visceral nociception: (1) electrical, (2) mechanical, (3) isehemic, and (4) chemical. Studies of visceral pain are discussed iu relation to the use and 'adequacy' of these stimuli and the responses produced (e.g., behavioral, pseudoaffective, neuronal, etc.). We propose a definition of an adequate noxious visceral stimulus and speculate on spinal mechanisms of visceral pain. Key words: Pelvic; Thoracic; Abdominal; Noxious; Afferents; Adequate stimuli; Pseudoaffective; Splanchnic; Clinical; Behavior; Spinal dorsal horn
Introduction
Clinically, pain is classified physiologically as superficial, deep or neuropathic. Superficial pain
Correspondence to: Dr. G.F. Gebhart, Department of Pharmacology, Bowen Science ~uilding, University of Iowa, Iowa City, IA 52242, U.S.A.
arises from the stimulation of cutaneous structures, d~.ep pain from stimulation of muscle, fascia, joints, bone, vascular structures and the viscera, and neuropatlfic pain from a disturbance of function or pathological changes in nervous tissue. Deep pain is of greatest clinical importance since pain from deep structures constitutes the majority of pain treated by the medical community. As opposed to superficial pain arising from cutaneous
0304-3959/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
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structures, which is well localized and evokes specific protective responses such as flexion reflexes, deep pains are characterized by poor localization, tonic increases in muscle tone, and a propensity to evoke strong autonomic responses such as changes in respiration, heart rate and blood pressure. Deep pains are also thought to evoke stronger emotional responses than superficia~ pains. As the intensity and duration of the stimulus increase, the subjective localization of deep pain becomes more generalized. That is, pain will radiate and be perceived as originating from a larger area, although the pain may become more intense at one site. Examples are pain originating from an inflamed joint, which may make an entire limb ache, or the pain typical of myocardial infarction: a dull pain/pressure located substemally which may spread to involve the entire chest and radiate to the shoulders, neck, jaw and down the ulnar aspect of the arms [446a]. Deep pains from bilateral structures (e.g., limbs, chest walls) are lateralized to one side and are roughly localized so that probing of sites that produce pain can localize 'point tenderness.' This is in contrast to deep pains from most of the viscera, which derived embryologically from midline structures (e.g., heart, gut, liver). Visceral pains are referred or 'transferred' to somatic (nonvisceral) structures near the midline, are more diffuse than other deep pains, and are not amenable to the localization of precise point tenderness until the pain-producing process (e.g., infectioninflammation) spreads and involves bilateral structures (e.g., the abdominal wall peritoneum). In addition to the phenomenon of referred pain, cutaneous and deep ti:~sue hyperalgesia also occur in association with visceral pain [e.g., 464a]. That is, skin and dee~ ti ~-.,cs become sensitized by an unknown process a~d previously innocuous somatic stimuli (e.g., stroking of the skin) may become painful. Because of its protean qualities, visceral pain is generally separated as a special case of deep pain. Pain originating in ore viscus cannot be easily differentiated from pain originating in another viscus by the quality, localization or intensity of sensation alone. Determination of the etiology of visceral pain is thus based on its generalized loca-
tion and clinical data such as rate of onset, aggravating factors and associated pathology (e.g., increased white blood cell count). A prime example of the poor differentiation of pain from a specific viscus is that of acute appendicitis. Based on the quality of the pain and locations where pain is sensed, the abbreviated differential diagnosis for this pathological condition listed in Cope's Diagnosis of the Acute Abdomen [428] includes the infection, inflammation, perforation/rupture, distension or torsion of the gallbladder, stomach, small intestine, colon, kidneys, ureters, pancreas, ovaries, fallopian tubes, psoas muscles or rectus muscles. Descriptions of some visceral pains have b~'en associated with specific etiologies. For example, pain from pancreatitis is typically intense and bores through to ,be back, pain from a dissecting aortic aneurysm is throbbing, pain from the intestines is crampy or colicky, and the pahl of a peptic ulcer is achy or burning. Unfortunately, visceral pain is unreliably 'typical' and the verbal descriptors of pain originating from a single viscus have been demonstrated to include words from every sub~oup of the McGill Pain Questionnaire [392]. The problem clinically is that pain originating from any of the viscera can be confused with pain from most other viscera end any statement that pain originating from a specific viscus is always of o,le type or localized to one body site demonstrates ignorance of the clinical experience of pain. For example, Staniland et al. [434] studied 600 patients presenting with an acute abdomen and reported that only two-thirds of the patients presented with symptoms that were 'typical' for the later determined etiology of their pain. There exists a wealth of clinical and older experimental literature which has addressed the subject of visceral pain and in recent years there has developed a renewed interest in behavioral, physiological and neurophysiological responses to noxious visceral stimuli. Investigations of visceral p~'m have addressed 5 main points [110]: (1) the nature of the adequate stimulus; (2) the site of its action; (3) the distribution of 'pain' nerve-endings in the viscera; (4) the peripheral and central nervous pathways which lead from ,dscus to sensorium; and (5) the 'mechanisms,' ~ t h physical and psycholo~cai, involved in die reference or localiza-
169
tion of visceral pain. The present paper summarizes some of the experimental literature related to visceral pain and suggests directions for future investigation.
Anatomy Viscerotomes
Just as cutaneous dermatomes are arranged according to the original arrangement of :issues in the embryo (Fig. 1), so too are ' viscerotomes' also arranged according to the original embryological location of the viscera. Viscerotomes are defined by patterns of evoked or pathological referred pain and by cutaneous and deep tissue hyperalgesia and the relief thereof provided by neurosurgical or local anesthetic procedures described in the clinical literature (Fig. 1). The heart, lungs, gut, liver, spleen, pancreas, gallbladder and urinary bladder all begin as midline tubes of mesoderm and endoderm which subsequently become convoluted, outpouched and thickened. The originally straight fore-, mid- and hindgut tubes lengthen, form loops and rotate 270 ° on a centred axis formed by the blood supply to the viscera. As a result, structures that originally were in the lower abdomen end up in the upper abdomen (and vice versa) and a somatotopic progression of the viscerotomes may not seem obvious. The viscera have a complex peripheral nervous system that allows for a wide variety of local autonomic functions. There is a dual innervation of the viscera, involving both cranial and spinal nerves, with secondary internet~rons in the medullary [e.g., 124,423,442] and spinal dorsal horns (see neuroanatomic references in Table It. Whereas cutaneous structures have sensory neurons that are located only in cranial nerve or dorsal root ganglia, the viscera have additional sensory neurons with cell bodies in and on the viscera themselves, in ganglia near the viscera (i.e., the prevertebral ganglia such as the celiac or inferior mesenteric ganglia), and may have cell bodies in the sympathetic chain along the vertebral colunto (paravertebral ganglia). Primary afferent neurons which transmit visceral sensory information to the spinal cord have cell bodies that reside in
the dorsal root ganglia. These primary afferents have distal processes that travel through the paravertebral ganglia, through the prevertebral ganglia and eventually have sensory endings in the viscera themselves. Large aggregations of these afferents are found in conjunction with motor fibers of the p~asympathetic nervous system in the pelvic nerve and with motor fibers of the sympathetic nervous system in numerous nerves. Fig. 2 is a schematic diagram of the gross anatomy of the visceral nerves of the human. Peripheral to the prevertebral ganglia, the continuation of visceral nerves is typically named by the organ innervated (e.g., renal nerve, rectal branch of the pelvic nerve). The phrenic nerve, originating predominantly at the C3-C5 spinal segments, is an additional pathway for visceral afferents from the diaphragm, liver, gallbladder, pericardium and pancreas [9,206,271]. The visceral nerve pathways identified above (i.e., through prevertebral ganglia, etc.) are based on gross anatomy and classical nerve degeneration studies [e.g., !50,258] that used light transmission microscopes to trace myelinated nerve fiber pathways. In recent years, anatomists have reexamined these earlier findings using the electron microscope and retrogradely transported neuronal tracers such as horseradish peroxidase and fluorescent dyes. Predictably, some previous assumptions of nerve pathways based upon gross anatomy and nerve degeneration studies have been found to be incorrect. For example, Hulsebosch and Coggeshall [219], using neuroablative and electron microscopic techniques, demonstrated that the pelvic nerve contains numerous sympathetic efferent fibers, a previously unsuspected finding. New visceral pathways also have been found. Sensory neurons with cell bodies in the rectum projecting directly to the spinal cord via the Lk,rsal roots have been reported [138a]. Another example is the existence of ventral root visceral afferents identified by neuroanatomical and dectr,,physiological techniques [106>107,109,165,324, 4121. The use of neuronal tracers has allowed for a precise, quantitative description of the spinal segmental distribution of afterents frot~l various organs, in various nerves, in numerous species.
170
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Fig. 1. Human viscerotomes: spinal segments m which visceral sensations are processed. A: illustration of human embryo and original relation between location of viscera and developing spinal nerves. B: examples of dcrmatomes corresponding to listed spinal segments. C: diagrammatic representation of presumed viscerotomes in humans as determined by the following: sites of 'referred" pathological pain ( ~ indicates typical dermatomes of referral listed in refs. 428, 439, 496; thickness of line relates to the frequency of occurrence); sites of cutaneous hyperalgesia associated with visceral disease ( - - - as in refs. 207, 286, 457); neurosurgical destruction of dorsal roots or local anesthetic blocks which lead to relief from pathological visceral pain ( . . . . . . , * indicates splanchnectomy effective in pain relief; from refs. 227, 410, 480-483, Lawen, 1923 and Hansen, 1963 both cf., 224); and sites of referred experimental pain ( . . . . . . , refs. in Table I). Abbreviations: Liv., liver; pane., pancreas; CI-TI-LI-S l, cervicalthoracic-lumbar-sacral spinal segments.
Studies in cats and rats are summarized in Figs. 3 and a, respectively. A similarly complete figure for the primate cannot yet be constructed since relatively few data are available [335].
Distribution of visceral afferents in the spinal cord A consistent finding of neuroanatomical studies of visceral afferent projections to the spinal cord is that they terminate predominantly in lamina I,
171
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deeper laminae (e.g., V and X) and adjacent to autonomic motor nuclei [130]. Visceral afferents appear to form a shell-like embracement of the dorsal horn with medial and lateral pathways that are 'repelled' by laminae IIi and III [349]. This has been documented for the greater splanclmic nerve [91,254,349], the colonic nerve [325], the least splanclmic nerve [347], the hypogastric nerve [326,347], the inferior cardiac nerve [256], the left renal nerve [255] and the pelvic nerve [324,334, 335]~ This disu~bution of primary afferents is consistent with electrophysiological studies demonstrating that spinal neurons excited by visceral stimuli are located predominantly in laminae I and II o and deeper laminae (e.g., IV-VII and X), but are largely absent from laminae IIi and III [e.g., 16,24,26,59,88,89,245,319,449]. The distribution of visceral primary afferents is similar to what has been demonstrated for fine afferents from other deep tissues such as muscle and joints [e.g.,
114,315], both of which are different from the sites of termination of afferents in nerves containing cutaneous afferents [e g. 2,91,349]. Afferents from cutaneous structures have numerous projections to all dorsal horn laminae with fine afferents terminating predominantly in laminae I and II o. Recently, the central terminals of intracellularly labeled axons of slowly conducting visceral and cutaneous afferents were compared in the guinea pig [444a]. Visceral afferents from the celiac ganglion had both ascending and descending central branches with collaterals that terminated ipsilaterally in laminae I, II, IV, V and X; some also gave collaterals into the contralateral laminae IV, V and X. Terminals of fine cutaneous affcrents, on the other hand, were concentrated in laminae I and II with a highly circumscribed ~nest-like' distribution (400 vm rostrocaudal distribution). Numerically, visceral afferents have been estimated to compose 5-15% of the neuronal
172
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Fig, 3, Feline viscerotomes: spinal segments of entry for visceral primary afferents in the cat determined neuroanatomically (solid line; thicker portions represent dorsal root ganglia of greatest labeling; refs. in Table i) or by functional studies (dots-dasht;s; refs. in Table !) in which pseudoaffective responses to visceral stimulation were abolished by dorsal root destruction (arrowhead indicates that the full caudal extent of entry wa~ not determined).
cell bodies in the dorsal root ganglia at the spinal segments receiving maximal visceral afferent input [92,254,349]. This is out of proportion to the relative number of spinal neurons which respond to Cervical Thoracic Lumbar Sacral I~1213141sl s]-~ el 11213141Sls171a19hob lh 2hal I 1213141s[ el t121 xl 4 ~J Phrenlc n. Greater Splanchnic n. Least $planchnlc/Hypogastrlc
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visceral afferent input at those same spinal segments, estimated to be 56-75% [e.g., 97], supporting the assertion that visceral afferent terminals are widely distributed in the spinal cord. Some visceral afferents also have been identified as projecting directly to the brain-stem [243,254,324, 347,349,429,497].
Dichotomizing primary afferents Another interesting finding is the possible existence of a small number of dichotomizing afferent fibers with sensory endings in both viscera and somatic structures. Pierau et al. [383] reported that 1.5-2.4% of the cell bodies of visceral afferents traveling in the greater splanchnic nerve of the cat could be double-labeled with retrogradely transported fluorescent dyes applied to the greater splanchnic nerve and a somatic nerve. Based on an observation by Alles and Dam [11], McNeill and Burden [309] reported that 7-15% of neurons labeled by injecting a fluorescent dye into the pericardial sac of the rat and located in the C8-T1 dorsal root ganglia were double-labeled by another fluorescent label applied to the left ulnar nerve. Similar convergence between the diaphragm and shoulder muscles has been reported [264]. The methodology of some of these studies was called into question by Dalsgaard and Ygge [122], who failed to identify more than a few double-labeled neurons receiving input from the splanchnic and thoracic spinal nerves; these investigators concluded that visceral and somatic afferents were separate populations. Supporting evidence for the existence of dichotomizing fibers has been given by electrophysiological experiments, demonstrating the existence of single afferent fibers that can be electrically activated from the pelvic and pudendal i~erves [198] or from thoracic visceral and somatic nerves [36]. The function of these dichotomizing fibers is unknown; they may contribute to the mechanism of referred pain [430,479]. However, fmlctional sensory endings have yet to be demonstrated for 'dichotomizing' afferent fibers. Neurotransmitters in visceral primary afferents Numerous neurotransmitters have been identified in visceral primary afferents, including sub-
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stance P and calcitonin gene-related peptide (CGRP) [e.g., 321]. An in-depth discussion of these neurotransmitters is beyond the scope of this review and has been well reviewed elsewhere [e.g., 131,138]. An interesting finding by Sharkey et al. [424; personal communication] is the existence of "clusters' of substance P and CGRP immunoreactive nerve te~:,~nals of visceral origin in lamina V of the sp; ~ c~rd. This finding is of especial interest to eleetrophysiologists who have noted that spinal neurons excited by visceral stimuli often are found in clusters [e.g., 60,97; Ness and Gebhart, unpublished] and correlates with findings of other investigators [130] that there is a periodicity of 300-1000/~m in the distribution of visceral primary afferents to laLnina V. Most neurotransmitters identified in visceral primary afferents also have been found in somatic primary afferents. However, vasoactive intestinal polypeptide has been suggested to be selective, if not specific, for visceral afferents, particularly those from pelvic organs [e.g., 216,235].
Functional identification of visceral afferent pathways An alternative to the neuroanatomical demonstration of primary afferent pathways is the 'functionar identification of these afferents. Functional identification derives from the stimulation of visceral afferents electrically or with other stimuli (e.g., distension or injection of algesic chemicals) in order to produce reflex responses such as changes in heart or respiratory rate and subsequently to abolish/attenuate these responses by selective neural lesions. The advantage of functional studies over direct neuroanatomical studies is that they may also give evidence of the sensory modalities of the afferents. That is, although there may exist afferents from the gallbladder at numerous spinal segments, the afferents encoding for distension of the gallbladder may enter the spinal cord at only a subset of these. As is demonstrated in Fig. 3, functional studies are in general agreement with neuroanatomical studies and in many cases are the only studies reported which define nerve pathways from certain viscera.
Electrophysiological studies of visceral primary afferents
Electrophysiologically, primary afferent neurons can be classified according to their response to natural stimuli, according to their conduction velocity, which suggests the presence or absence of myelination and diameter of nerve fiber, or according to their central sites of projection. Few electrophysiological studies have examined the central sites of projection of functionally identified ,visceral afferents and so the work of Downman and Evans [145] and Schramm and associates [243,244,429] deserves special notice in that these investigators characterized visceral afferents for their responses to natural stimuli, their conduction velocity and their central sites of termination, which were both spinal and medullary w~th axons traveling rostrally in the dorsal columns. Numercus visceral afferents have been characterized for conduction velocity,and responses to natural stimuli and the characteristics of these neurons will only be brieflydiscussed as this literature has been reviewed elsewhere [29,222,224, 253,265,268,290,312,313,330,331,368,416].In general, most visceral afferents have relatively slow conduction velocities(i.e.,are thinly myelinatcd or unmyelinated nerve fibers). The relation of activity in primary afferents to visceral pain sensation is still poorly understood, due in part to the absence of agreement on definition of an adequate, noxious, visceral stimulus. The most sigrdfieant result of quantitative electrophysiological studies of visceral afferents is the virtual absence of specific nociceptors. That is, primary afferents dedicated to nociception with high thresholds for mechanical activation and/or selective chemosensitivity have not been identified as a distinct subclass of visceral afferents, alt h o u ~ afferents of differing sensitivities have been described [339]. General!,y, visceral afferents such as those from the colon traveling in the least splanchnic nerves of the cat have been found to be polymodal, giving excitatory responses to bradykinin, KCI, hypertonic saline, ischemia and to colonic distension with intraluminal pressure thresholds for response near 0 ram Hg [64,205]. Sirrfil~r
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polymodal afferents from the testis [253] and from the heart [290] have been characterized, which has prompted various investigators to assert that visceral pain is due to the intensity or pattern of visceral primary afferent activation [e.g., 224,290]. One general criticism of most studies of visceral afferents is that they typically have recorded from sensory fibers in peripheral visceral nerves. Sensory fibers which do not project to the spinal cord, but only to para- or prevertebral ganglia [e.g., 239], are :herefc,re contained in these samples of nerve fibers and may constitute a majority of the sensor)' fibers present. Since these fibers are likely involved in local autonomic processing of non-noxious stimuli, the failure to identify specific visceral nociceptors may reflect their proportionately small number in the periphery. Another consideration is that virtually all reports to date have studied 'normal' non-inflamed tissue, a circumstance where nociceptors may be silent (see below). Several studies, however, have suggested that specific visceral nociceptors may exist since visceral afferent fibers with high mechanical thresholds for activation have been identified. Cervero [87] characterized 2 classes of afferents from the gallbladder and biliary tract of the ferret: one population was excited at low pressures of distension and the other was not excited until the gallbladder was distended by pressures sufficient to evoke cardiovascular responses. Earlier, Gernandt and Zotterman [182] studied gastrointestinal 'nociceptors' with high mechanical thresholds for activation in multifiber recordings of afferents in mesenteric nerves, as did Clifton et al. [106] in recordings from lumbosacral ventral root afferents. Morrison and associates [164,166, 329,330] also may have identified gastrointestinal nociceptors wher~ they recorded from visceral afferents that responded vigorously only to stimuli which produce pain in humans (i.e., contractions or overdistension of the large intestine and traction on the mesentery). While these studies support the existence of visceral nociceptors,, it may be that the high threshold group of afferents from the gallbladder characterized by Cervero or the gastrointestinal 'nociceptors' charactedzed by others may be the tail of a normal distribution of a single population of non-specific, polymodal
visceral afferents as suggested by J~fig [224; personal communication]. Alternatively, specific nociceptors may exist for some (e.g., gallbladder), but not all viscera or be normally silent. There exist afferent fibers from deep structures (e.g., joints, viscera) which can be activated by electrical stimulation but not other, natural stimuli (i.e., they are 'silent' normally). In circumstances of experimentally induced inflammation, these silent nociceptors can be activated by stimuli previously ineffective. Thus, specific nociceptors in deep tissue may exist but only become evident when tissue pathology is present. Experimental studies, of course, are generally carded out in 'normal' subjects which would significantly underestimate the presence of specific nociceptors since tissue pathology is not present.
Adequate visceral stimuli and nociceptive responses Defining an adequate noxious stimulus for studies of visceral nociception has been a significant obstacle to quantitative experimental studies of visceral pain. Adequate stimuli are those that optimally and/or naturally produce a given sensation. Sherrington [425] defined 'nocuous' stimuli as those that produced tissue damage or nredicted tissue damage. For cutaneous structures, this definition is consistent with stimuli painful to humans. However, non-inflamed viscera in humans often can be cut or burned (tissue damaged) without producing pain. This prompted numerous investigators, who performed procedures utilizing local or regional rather than general anesthesia [e.g.,286,287; Lennander, cf., 273], to claim that the viscera were insensate and that visceral sensations resulted from the irritation of the parietes (lining of chest/abdominal wall). However, many of these early studies were confounded by the use of morphine as a prctreatment or excessive doses of cocaine as a local anesthetic. Numerous subsequent studies have clearly established that pain can originate from the viscera, but that cutting, burning or highly localized mechanical stimuli may not be adequate stim,.di. For example, Kinsella [241] evoked reports of pain by squeezing the entire length of isolated, inflamed appendices.
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Pinch of a 2-3 mm stretch of the same appendices using a fine forceps in the same patients caused no pain. Consequently, noxious visceral stimuli are defined here as those stimuli, preferably natural, which produce visceral pain in humans and behavioral responses in other animals typically associated with tissue damaging cutaneous stimuli in animals (e.g., escape, avoidance, etc.). Ideally, an adequate noxious visceral stimulus also should be reproducible, easily controlled to provide quantifiable, graded stimuli, and minimally invasive to limit the influence of experimental methodology on the resuKs. A nociceptive response to an adequate noxious stimulus is one that is consistent with what is observed clinically in humans and occurs in response to that stimulus or other adequate noxious stimuli. Commonly measured nociceptive responses are the pseudoaffective responses characterized by Sherrington and coworkers [425]. Pseudoaffective responses are brain-stem or spinal reflexes which suggest an emotional or affeetive response to tissue-damaging cutaneous stimuli or, by the above definition, to noxious visceral stimuli. These responses include flexion/withdrawal and head-turning with lateralized somatic stimuli and grimacing, vocalization, cardiovascular changes, respiratory changes and generalized or regional muscle contractions with non-lateralized somatic or visceral stimuli [490]. Pseudoaffective responses cease when the noxious stimulus is terminated. Examples of cardiovaseu-
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Respiratory ! Ol=tenslon 80 mmHg
i
Fig. 5. Pseudoaffective responses. Examples of visceromotor (top, electromyogram (EMG) of external oblique musculature), cardiovascular (middle recordings) and respiratory (bottom, plethysmographie record) responses to colorectal distension (80 ram Hg, 20 sec) in an awake unanesthetized rat [see 342 for full characterization].
lar, respiratory and visceromotor pseudoaffective responses to noxious colorectal distension in the rat are illustrated in Fig. 5.
Organization of the review Experimental studies of visceral nocicepfiot~ have used as stimuli electrical shocks, mechanical distortion (e.g., distension of hollow organs), ischemia and algogenic/irritant compounds. Given the importance of the stimulus, experimental studies of visceral nociception are discussed under the headings of these 4 stimuli rather than by organ. Studies in man and those in other animals measuring behavioral, autonomic and electrophysiological responses are reviewed. Because the modulation of responses in animals is often used to define a stimulus/response as noxious/nociceptive, studies related to the modulation of visceral pain are also considered. Subheadings will allow the.reader to focus readily if desired. A listing of selected references by organ is given in Table I. The review is limited to studies employing mammalian species, although numerous interesting results have been noted in amphibians and reptiles [e.g., 81]. This review will only briefly discuss studies related to the activities of preganglionic spinal autonomic motor neurons that receive numerous visceral and somatic inputs [e.g. 132,223]. Discussions of cutaneous receptive fields of spinal neurons will use the class 1-3 terminology where neurons are defined as class 1 if only excited by non-noxious stimuli applied in their cutaneous receptive fields, class 2 if excited by both noxious and non-noxious stimuli, and as class 3 if only excited by noxious stimuli. This nomenclature is not ideal since it does not take into account inhibitory cutaneous receptive fields, responses to stimulation of non-cutaneous tissues or gradation of stimuli/responses; it does, however, allow for a qualitative comparison of the studies performed to date. What constitutes a noxious stimulus in nonhuman animals is always arguable and was often not defined in many of the studies described in tiffs Jeview. Based on statcments in the methods sections of studies from various laboratories, non-
Adson, Leriche, Foerester (cL, 273, 391)
141,494, Lerich~ Jonnesco (cL, 273,391)
267,405
Thoracic visceral nerves
Pelvic visceral
48,63,66,7% 101, 137a, 240 262,278,327, 391,492
Small intestine
Stomach
41, 46, 51, 101, 102, 209, 240, 251, 278, 327, 332, 373, 374, 384, 391, 395, 477 63, 66, 80, 332, 391
Esophagus
llerves
ilerves
Abdominal visceral
Human
210,348
43-45,198, 235, 301, 324-326, 334, 335, 347
15Z191,25~ 264,361,411
36, 91, 92, 122 153, 254, 349, 383
Neuroanatomic
Spinal: 192 Other: 82, 116, 226, 380
85,151,226
180,181
Spinal: 14-17d, 21, 24, 27a, 86-90, 94-98, 159, 170, 187, 188, 199, 200, 245, 372, 385, 409, 421, 422, 450, 451, Other: 5, 12, 13 82, 85, 143, 145, 303, 351-355, 378-380, 406, 407, 459, 486, 500 Spinal: 18-27, 57-61, 68, 69, 99 100, 168, 169, 171, 172, 192a, 214, 449, 456, 476 Other: 448, 499, 5OO 129, 132, 133, 307, 308, 500
Neuronal
146,151, 194, 281,283-285, 302, 310, 387, 420, 438 65, 104, 146, 147, 174, 194, 201, 202, 231, 237, 269, 274, 310, 311, 360, 363, 414, 420, 438, 440, 441, 474
146,415
4, 261,419
4, 74, 248, 293, 294, 381,471
1, 4, 6, 7,~ 105, 125, 146, 228, 370
Cardiovascular
146, 322
146, 194, 317, 322
34, 111, 112 133a, 146, 147, 194, 274, 317, 322, 467
194, 322, 413, 420, 469
34, 47, 117, 191a, 194, 322, 388, 413, 420
77,175,176, 317,498
322,415
4,175,176, 418
77,211
8, 33, 34, 40, 77, 105, 125, 144, 146, 147
4, 7, 33, 34, 125
4,211
Visceromotor
Respiratory
Pseadoaffective responses
SELECTED REFERENCF~; TO EXPERIMENTAL STUDIES OF VISCERAL PAIN LISTED BY NERVES/ORGANS
TABLE I
147, 206, 310
206, 310
206
4
4, 37
Nict./pupil. a
52,101,120, 140,179,212, 266, 271, 299, 300,332, 359, 390, 391,420, 501-503 431,493 71a, 225,247, 455
Biliary system/liver
10, 221,446a
Heart, lungs and related structures
119 12,, 309 464
49, 242, 336
9, 42, 220, 289
103,139,255
3~ 142
138a, 336, 343
Spinal: 18, 22, 25, 27, 57, 58, 60, 61, 68, 69, 99, 171,456, 476 Other: 53-56
233,319 133,250,389, 401,402 Other: 217
20, 23, 86, 89, 158,160,371
69,73,93, 129o132,133, 151,158,159, 215, 232,305, 307, 308, 319 Spinai:14-17d, 27a, 214,245
Spinal: 73, 129, 132, 133, 158160, 215, 307, 308, 340, 341, 343-346 Other: 151, 177
a Nict./pupil. indicates nictitating membrane or pupillary response (e.g., dila~ion).
328, 391
Pancreas
Spleen
Male reproductive Female reproductive
358, 391,464a 475
63,79,136,149, 155,189,213, 229,230,236, 240,241,262, 263,272,278, 327,391,397-399 446,484 120,134,193 337,391,495
Kidney and ureters
Urinary bladder
Colon/rectum
75,105,146, 194, 275, 311, 458 146, 274, 364, 414,468 71,84,156,157, 190,192a, 194, 2O4,234,252, 289, 293, 294, 296, 339, 356, 365,366,394, 435-437,445
233,320 146,175, 25;
1, 16-17d, 67, 74, 185, 224a, 249, 260, 37~, 432, 462, 490 23, 35, 86, 87, 89,119, 194, 322, 351, 362, 364, 420, 438, 443, 468, 490
151, 175, 186. 333, 419, 426, 452-454, 470, 472
123,151,175, 342,454,470
70,234,298, 322,323,376, 445, 481,482
7, 274
194,275,322
233,320 175,257
126,128,167, 194,322, 413, 420,443,469
322
]54,175,31~ 333,418
175,322,388
70, 234, 298, 322, 323, 376, 445, 481,482
146
146, 194, 317, 322
115, 146, 175
33, 34, 194, 443
317, 322, 490
3, 154, 175, 305, 306, 314
115,123,175, 227,288,316318,322,342, 433,490
70
206
206
206
470
206, 470
178
noxious stimuli include hair movement and fight pressure (e.g., brush, air puff) and noxious stimuli included pinch, crush, pin-prick and heat, all presumably at intensities sufficient to produce pain in the investigators. The terms 'visceral' and "somatic' will be used throughout this revie~v; somatic refers to all structures that are not internal organs and includes skin, muscle, joints, bone and connective tissue. The oral and nasal cavities, pharynx, vaginal introitus, outer urethra and anal canal all fall within a gray zone of the visceral or somatic distinction and so are generally not discussed.
Electrical stimulation as a noxious visceral stimulus
General Electrical stimulation of isolated nerves or organs is a reliable reproducible stimulus, but is not specific for any sensory modality. It has been suggested [e.g. 90,97] that spinal neurons excited by visceral afferents to the thoracic spinal cord traveling with sympathetic motor fibers can only be excited by noxious intensities of stimulation. If this assertion is correct, then electrical stimulation of these visceral nerves is ideal as a noxious stimulus since its non-specificity becomes irrelevant; excitation equates with nociception. Support for this simple assertion is given by electrophysiological evidence that only fine afferents from the viscera terminate in the spinal cord. Since fine afferents are assumed by many to carry information related only to nociception, a logical extension of this assumption is that all spinal neurons excited by electrical nerve stimulation are receiving noxious visceral inputs. 'Non-noxious' conscious sensory events, such as pressure or movement of gas in the bowel, must therefore be (1) due to pathways that travel through, but do not terminate in the spinal cord (e.g., dorsal column pathways); (2) actually 'painful' but not recognized as such; (3) due to activation of somatic abdominal wall sensory receptors; or (4) due to the activation of visceral sensory fibers travding in conjunction with parasympathetic motor fibers (e.g., vagus nerve). Numerous visceral sensations (e.g., stomach, rectal or bladder fullness, nausea) do travel
by such 'non-spinal' routes [488]. However, reports of spinall~ mediated, presumably non-nociceptive reflexes evoked by the natural, physiological stimulation of visceral afferents traveling in conjunction with sympathetic motor fibers argue that not all spinal processing of visceral afferent input is nociceptive [e.g., 228,367]. Numerous electrophysiological studies employing more natural stimuli such as probing of the heart [e.g., 57], distension of the gallbladder [20,23], distension of the urinary bladder [133,307,308] or distension of the c o l o n / r e c t u m [307,308,340,343,345] have demonstrated that there exist spinal neurons excited by presumably non-nociceptive intensities of visceral stimulation. With the caveat that experimental manipulations might make visceral primary afferents a n d / o r spinal visceral nociceptive neurons 'hyperalgesic,' and hence responsive to previously non-noxious intensities of visceral stimulation, the assertion that visceroceptive neurons in the spinal cord respond only to noxious intensities of visceral sensation is an overgeneralization as non-nociceptive, visceral inputs certainly can result in visceral sensation. Although electrical stimulation of the main visceral nerves provides an artificial stimulus which is neither organ- nor modality-specific, ample evidence for the utility of electrical stimulation as a noxious stimulus is given by human studies in which electrical stimulation of visceral nerves [Adson, cf. 391; Leriche, Foerester and Jonnesco, cf., 273; 141,267,405,494] or of the viscera themselves (biliary system [391,503], kidney/ureters [358,391], pancreas [391], gastrointestinal tract and associated membranes [66,78,391]) has consistently demonstrated that pain can be produced in most patients when the intensity of the electrical stimulation is sufficient to activate small diameter afferent fibers. Non-painful sensations also have been noted with electrical stimulation [e.g., 405], but electrical stimulation of visceral nerves without current spread to somatic tissues cannot be ruled out as a possible confounding factor. In humans, pain secondary to electrical stimulation of the various viscera was localized to regions consistent with what is observed in pathological referred pain. In addition to the effects of direct activation of visceral primary afferents, electrical stimulation
179
of the stomach or Oaodenum has been noted to produce spasm of these organs [66], which itself may produce pain. The characterization of spinal neurons responsive to visceral nerve electrical stimulation includes their location, rostral projections, conduction velocity of primary afferent input and characterisfcs of somatic input. A limitation of studies employing electrical stimulation of visceral afferents is that they do not allow for an assessment of changes in the sensitivity of the primary afferents due to peripheral mechanisms (e.g., inflammation), which clinically appears to be a major mechanism related to the etiology of pathological visceral pain. Experimental studies in which visceral nerves were stimtlated to produce neuronal or pseudoaffective responses can be grouped into 3 categories according to the nerves stimulated: abdominal visceral nerves, thoracic visceral nerves, and pelvic visceral nerves. As these studies are numerous, each category will be subgrouped according to the index of measurement (i.e., reflex or neuronal indices). Abdominal visceral nerves Reflex indices. Electrical stimulation of the greater (major) splanchnic nerves (left and right) has been commonly employed in studies of visceral sensation. These nerves contain afferents from most of the gut, the biliary/hepatic systems, the pancreas, the spleen, the kidneys, testis/ovaries and pelvic organs via the hypogastric nerve. Hence, electrical stimulation of this nerve is not organspecific and clearly activates numerous visceral afferents. Woodworth and Sherrington [490] first demonstrated that stimulation of the greater splanchnic nerves produced pseudoaffective responses consisting of viscerorn~tor responses and vocalization. Subs'e2iuent researchers have verified these findings by demonstrating that electrical stimulation of the greater splanchnic nerves [4,8,32~34,37,77,125,144,146,433] and branches of the splanchnics such as the celiac nerves [316], gastric nerves [317], hepatic nerves [3"._7], pancreoduodenal nerves [7], mesenteric nerves [228, 316-31[~,388], splenic nerves [105,317], renal nerves [1,74,260,370], testicular nerves [320] and ovarian nerves [257] will produce nictitating mere[ r a n e /
pupillary responses [4,37], visceromotor responses [8,33,34,77,105,125,144,146,316-318], alterations in respiration [4,7,34,125,257,320,388] and cardiovascular responses [1,4,74,105,125,146,228,257, 260,320,370]. By making lesions in the spinal cord and using pseudoaffective responses to electrical stimulation of the greater splanchnic nerve as a guide, Woodworth and Sherrington [490] and Davis [125] demonstrated that the spinal pathways for the production of pseudoaffective responses projected bilaterally, but predominantly in the anterior/lateral columns of the contralateral side. Davis further stressed the importance of short relays within the spinal cord since the only way to abolish the cardiovascular responses to nerve s~.imulation was complete spinal cord transection. Downman [144] reported that afferents traveling in the greater splanchnic nerve entered the spinal cord and ascended at least 4 segments. Johansson and Langston [228] characterized cardiovascular responses to nerve stimulation and determined that stimulation of high (electrical) threshold afferems in mesenteric nerves produced pressor responses; depressor responses were noted at lesser intensities of stimulation. These investigators also noted that high intensity stimulation of the mesenteric nerves produced a reflex vasoconstriction in kidneys and decreased mesenteric and skeletal muscle blood flows. Studies by Bardos and associates [39,40] examined behavioral responses to electrical stimulation of the stomach or small intestine (mucosal electrodes). They found that rats were able to discriminate the presence or absence of stimulation u~ing an operant behavioral paradigm and exhibited behavioral reactions that were consistent with the interpretation that electrical stimulation was aversive. Earlier, Cannon [77] examined the effects of greater splanchnic nerve stimulation in unanesthetized cats and observed visceromotor responses and vocalization, suggesting that electrical stimulation was noxious in character. Cannon also stimulated the lumbar sympathetic chain and got similar responses, but observed no behavioral responses with stimulation of the vagus nerve below the level of the recurrent laryngeal nerve or 6.:f ~ e sympathetic chain above the superior cerv:,caJ ganglion.
180
Neuronal indices. Numerous investigators have recorded from neurons responsive to electrical stimulation of abdo~vdnal visceral afferents that have cell bodies located in the spinai cord or supraspinal structures such as the thalamus [5,82,303,499,500], hypothalamus [5], cerebral cortex [12,13,116,143,352,459], cerebellum [353355,378,406,407,486] or medullary structures [e.g., 379,380]. Pomeranz et al. [385] demonstrated that spinal cord neurons in the deep laminae (presumably lamina V) of the thoracic spinal cord responded to both splanclmic nerve stimulation and natural cutaneous stimuli. Although visceral nerves also contain relatively large myelinated fibers with pacinian corpuscles for endings, these investigators were unable to identify any spinal neurons that responded to intensities of splanclmic nerve stimulation sufficient to activate only these fibers. The neurons studied had relatively large cutaneous receptive fields in comparison with neurons receiving only somatic input and responded, in general, to both noxious and non-noxious cutaneous stimuli. Gokin and associates [187,188] extended these findings to include viscerosomatic neuruas in the superficial dorsal horn and ventral horn of the thoracic spinal cord of the cat; others examined the cutaneous receptive fields of the spinal neurons quantitatively [96,98] and also have demonstrated the existence of long ascending projectior, s of visceroceptive spinal neurons to the brain [88,98,170,199,409]. Although a s,abset of visceroceptive spinal neurons with long ascending projections reaches the thalamus, the precise sites of termination of all visceroceptive neurons with long ascending projections have never been quantitatively determined. However, work by Cervero [88] suggests that most spinal neurons excited by electrical stimulation of the greater splanchnic nerve with long ascending projections to the brain have axons in the contralateral ventrolateral quadrant of the cervical spinal cord. Cervero also identified neurons with projections via the ipsilateral dorsolateral funiculus and others w~ih projections to the cervical spinal cord, but no visceroceptive spinal neurons have been identified as postsynaptic in the dorsal columns. Hence, spinal neurons receiving visceral inputs have patterns of distribution of projection similar to those
of somatic nociceptive spinal neurons. A more complete discussion of visceral inputs to specific sensory pathways is reviewed elsewhere [488]. Neurons excited by the electrical stimulation of the greater splanchnic nerves have been found in virtually every spinal segment. Akeyson enid Schramm [6] recorded from spinal neurons in the cervical spin~ cord of the rat that were responsive to electrical stimulation of the greater splanclmic nerve. Similarly, Hancock et al. [200] reported that neurons it~ the L6-L7 spinal segments of the cat also could be excited by electrical stimulation of the greater splanchnic nerve, even though afferents from this nerve enter the spinal cord roughly 10 spinal segments rostral [92,254]. Ammons and associates [21,24] also characterized neurons in the upper thoracic spinal cord that were excited by electrical stimulation of the greater splanchnic nerve. In 7 primate spinothalamic tract neurons with cell bodies in the T1-T5 spinal segments, they [21] demonstrated that a transection of the left sympathetic chain between the T5 and T6 ranti communicantes reduced the number of discharges to left splanchnic nerve stimulation by 27%. Sectioning of the sympathetic chain more caudally further reduced the neuronal response until, by the TS-T9 gap, 71% of the response to splanchnic nerve stimulation had been abolished. Additional lesions of the dorsolateral column of the spinal cord caudal to the recording sites had little additional effect on the neuronal responses, whereas lesions of the lateral and ventrolateral columns reduced or abolished the neuronal responses. In this way, it was determined that visceral afferent information traveled to the T1-T5 spinal segments by both extraspinal (sympathetic chain) and intraspinal routes, h~traspinal primary afferent pathways traditionally consist of Lissauer's tract and neighboring dorsal and lateral funiculi. However, the work of Ammons et al. [21] suggests that this is not the intraspinal pathway for visceral afferent information traversing four or more spinal segments. Other 'intraspinal' pathways conveying visceral afferent information have been demonstrated by Pavlasek and Duda [372] for descending excitatory inputs to lumbar spinal neurons from greater splanclmic nerve stimulation (propriospinal and spinobulbospinal pathways).
181
"!"aese pathways may have been the substrates for some of the ascending excitatory input to the upper thoracic spinal cord ,~ser~ed by Ammons et al. [21]. No matter wtv~t the precise routes for excitation are, it is apparent that the stimulation of a single visceral nerve, unlike stimulation of a somatic nerve, cma lead to the excitation of neurons in widespread segments of the spinal cord. In addition to the greater splanchnic nerves, other abdominal visceral nerves also have been electrically stimulated to identify visceroceptive spinal neurons. Seizer and Spencer [421,422] recorded from neurons in the middle to upper lumbar spinal cord segments excited by electrical stimulation of the sympathetic chain. Fields et al. [158] similarly demonstrated that sthnulation of the white rami communicantes of the sympathetic chain activated neurons in the upper lumbar spinal cord. Recently, Ammons in the cat and primate [14-17d] and Kneupfer et al. in the rat [245] electrically stimulated the renal nerves to activate spinal neurons, many of which had long ascending projections to the brain. Viscerovisceral and viscerosomatic convergence have been the rule rather than the exception in studies of spinal neurons excited by electrical stimulation of abdominal visceral and/or somatic afferents (Table II). For example, 100% of the neurons characterized by Ammons and Foreman [23,2,[' that responded to electrical stimulation of the !:~t splanclmic nerve also responded to electrical stimulation of thoracic visceral nerves. Only a few neurons described by Cervero [89], Ammons [15,23,24] and others [187,188,245] have had identifiable visceral inputs without identifiable convergent excitatery somatic receptive fields, some having no resl:onses to somatic stimuli whatsoever [89,187,18~,245]. Convergent cutaneous receptive fields were generally described as multidermatomal, centered in the dermatome corresponding to the spinal segment of study, and were significantly larger than the receptive fields of spinal neurons ~receiving only somatic input [9698]. The classification of visceroceptive neurons by their cutaneous receptive fields differs between laboratories, wtfi,ch suggests significant differences in species, preparation, technique and/or method of classification. This is of importance as the
classificatJ~'~ of ne onai types has bearing on the presumed function of these neurons. For example, t,:: ¢:~,nction of visceroceptive neurons that are of the class t type, responsive only to non-noxious cutaneous s~h'nuli, is questionably nociceptive. Ammons and Foreman [14-16,23,24] described neurons responsive to splanchnic nerve stimulation as predominantly class 3, responding only to noxious cutaneous stimuli; they found no class 1 neurons in their samples. In contrast, Cervero and associates [88,89,94-98,450,451] described neurons responsive to the same stimulus as predominantly class 2, responsive to both noxious and non-noxious cutaneous stimuli, but also characterized numerous class 1 and class 3 neurons that also were excited by visceral afferent stimulation. Given the importance of neuronal classification to assessing function of neurons, differences such as these make a precise formulation of the function of visceroceptive neurons difficult. Thoracic visceral nerves Reflex indices. Thoracic viscera include the
esophagus, heart, lungs, thymus and other lymphoid tissues, the diaphragm and the vessels and membranes surrounding these structures, including the pericardium and visceral pleura. The afferent nerve fibers from these organs to the spinal cord travel in the phrenic nerve and enter the upper cervical spinal segments, in the cardiac nerves that traverse the upper sympathetic chain, including the ~tellate ganglion, and enter the upper thoracic spinal segments, and in the thoracic splanchnic nerves (which are small branches of the thoracic ganglia of the sympathetic chain) and en*.er in multiple thoracic spinal segments. Since the heart is the most common source of clinically significant visceral pain from the thorax, numerous studies have electrically stimulated thoracic afferent visceral pathways such as the inferior cardiac nerve or the steUate ganglion and considered excitatory responses to be representative of cardiac or cardiopulmonary i~put, although afferents fr~rn other thoracic viscera may have been the source of excitation. Electrical stimulation of these afferents leads to significaL~t alterations in sympathetic efferent outflow, measured as cardiovascular changes [e.g., 248,381] or ch,~nges in sym-
Recording site
n
T2-4
T8-9
T8-9
T8-9
T8- i 1 T9-11 "1"9-11
T10-11 T11 T10-L2 Thoracic Thoracic T1-5
Cat
Cat
Cat
Cat
Cat Cat Cat
Cat Cat Cat Cat Primate Primate
T10-L1
T12-L2
TI2-L2
T12-L2
Rat
Cat
Cat
Cat
Renal nerve stimulation
T2-4
Cat
97-100%
?
61 64
100%
100%
84%
100% 100% 100% 100% 100% 100%
100% 1.00% 100%
100%
100%
96~
95%
98%
% ,u)nv. j
20
65
88
58 29 6 10 15 63
44 78 83
165
92
82
56
65
Greater splanchnic nerve stimulation
Species
VISCEROSOMATIC CON VERGENCE
TABLE II
excited excited (58) d grouped with inhibited (3) '~
[151
[161
[14l
0
0
0
0 0
13
12
10
10 0
33
4 3 11 29
0 2 2 0
0
0 4~ ?
0 3 ?
excited excited excited excited excited excited excited excited (83) d grouped with inhibited (5) excited inhibited
14 37 13 14 8
18 76 20 42 20
4 16 11 22 3
excited excited excited excited excited
44
36
10
36 4
8
0 5 2 34
3 11 ?
?
?
?
39 8 6 12 0 31 30
Class 3
excited
Class 2 7 1 1 5 1 4 42
Class I
Somatic classification b
0 0 0 0 0 0 7
excited inhibited excit./ir,hib. excited inhibited ? excit.ed
Response to stim.
[2451
[199] [170] [21]
[88] [951 [4091
[45o,451] [94]
[96]
1981
[86]
[89]
[231
[2q
[refl
3-inhibited 10-deep 5-deep 2-.'?
8-visc. only 50-.'? 9-deep 1-deep 5-inhibited
2-deep
lO-deep 33-7 6-?
3-inhibited 3-visc. only
1-inhibited 2-inhibited
Other
neurons neurons neurons neurons
SRT neurons; some excited by renal venous or ureteral occlusion
SRT neurons
STI" neurons
SIT STT SIT SIT
unilateral GSN input
bilateral GSN input
Some excited or inhibited by gallbladder dist. Some excited by gallbladder dist. Some excited by gallbladder dist. Lamina I neurons Deep laminae neurons
Comments c
T1-4
T2-4
T2-4
"1"2-4
T2-4
T2-4
T2-4
T2-4
Cat
Cat
Cat
Cat
Cat
Cat
Cat
Cat
135
64
40
58
72
101
64
61
92-9455
10055
9555
9755
96~
.9
95-10055
10055
100~g 97~$
[171]
[61]
[57]
[476]
[24]
[169]
[23]
[100]
[168] [456]
excited
excited
excited
excited inhibited excit/inhib. excit,~d
?
'~
excited
excited excited
14
5
3
1
15 1
8
10
27
5
99
33
39 8 6 53
68
51
34
,9 22
2g 33
?
TI-4 T1-3
Ca1 Cat
14
18
2;2
0
[17d]
18
44
46
32
100.~
[17c]
excited (62) d grouped with inhibited (6) excited
12
26
54
10055
[17b]
excited
11
T1 l - L 2
Primate
38
100~
[17a]
Thoracic visceral nerve stimulation (inferior cardiac or sympathetic chain) Cat T1-4 69 10055 [449] excited
Tll-L1
Primate
68
1005
40
T10-L3
Primate
66
excited
T12-L2
Cat
11-deep 8-inhibited 3-7
2-visc. only
2-inhibited
2-visc. only 22-.9 2-inhibited
3-inhibited
1-visc. only 1-7
2-deep
2-deep
8-deep
Some excited by bradykinin Some excited by PVCs or other cardiac mechanical stimuli STT and SRT neurons; some excited by bradykinin 4555 respond to CAO
Some respond to GSN stbn.
SRT neurons modulated by vagal stim. SRT neurons modulated by NRM stim. Also excited by gallbladder stim. SRT and STI" neurons
Cell bodies in laminae I, I!o Cell bodies in lawl.-~ae IV-VI
S'IT neurons; some excited by ureteral occlusion S I T neurons; some excited by renal pelvis distension
S T r neurons
Some excited by renal venous or ureteral occlusion
T2-6
C8-T5
C8-T5
Upper Thoracic T1-4
T1-5
T1-5
T2-4 T2-5
T2-5
T2-5
T2-5
T3-5
T3-5
Cat
Primate
Primate
Primate
Primate
Primate
7/anate Primate
Primate
Primate
Primate
Primate
Primate
axons + S1
T2-4
T8-9
Cat
Cat
Gallbladder atstension
Cat
Pelvic visceral nerves
Primate
Recording site
Species
TABLE II (continued)
28
26
110
31
30
41
42
58
9 38
45
85
42
31
69
41
84
100%
100%
50%
100%
100%
98%
98-100%
100%
100% I00%
100%
100%
I00%
100%
1(10%
100%
100%
% conv. a
excited
.9
excited
?
.9
excited excited
excited
excited
excited
excited
excited
excited
excited
Response to stim.
[86]
[23]
excited inhibited excited
[307,308] excited
[59]
[18]
[69]
[27]
[26]
[172] [25]
[21]
[20]
[22]
[68]
[19]
[60]
[99]
[req
7
0
0 0 ?
.9
0
?
5 1 .9
.9
8
7
25
17
2
1
9 14 8 4
? ?
29
35
0 2 2 0
0 .9
1
1
27
?
? 1
25
?
? 0
24
Class 2
0
Class 1
Somatic classification b
12 8 .9
.9
23
?
14
2
3
15 5 3 6
? ?
15
49
14
?
44
?
60
Class 3
1-?
m
1-inhibited
n
Other
35/40 with visceral mechanical fields had cutaneous input
Some SRT neurons; rome excited by bradykinin; total modulat, by PAGS STF neurons; some excited by bradykinin S'VF neurons modulated by vagal stim. STT neurons modulated by SC-PB stim. STT neurons modulated by N R M stim. S T r neurons; some excited by fallbladder stim. STT neurons; some excited by GSN stim. STT neurons Medial and lateral STF neurons; some excited by bradykinin Medial S I T neurons Lateral S I T neurons Med.-lat. tiFF neurons Medial STI" neurons inhibited by PVGS Lateral s T r neurons inhibited by PVGS Med.-lat. tiFF neurons inhibited by PVGS STF neurons, some inhibited by urinary bladder dist. STF neurons modulated by vagal stim. STI" neurons
Comments c
O0
T8-9 T1-5
C8-T5
S1-3
Lumbar
TI2-LI L7-$3
Cat
Rat
Primate
L6-S1 T12-L1
S1-3
Lumbar
T13-L2
L6-$2
Cat
Rat
Rat
Rat
107
177
33
30
8
? 17
19 17
20
72
12
42
30 17
49~
97~$
100%
83~$
100~$
50% 100%
100% 100~$
100~$
81~$
100%
100~$
100% 100~$
excited excited inhibited
excited (5) inhibited (7) excited inhibited excited inhibited excited
excited (27) inhibited (1) no response (14)
excited ?
inhibited
excited (7) inhibited (1) [215] excited inhibited [73] excited inhibited [343,345] excited excited inhibited [340] excited
[158]
[233] [319]
[319]
[73]
[215]
[158]
[58]
[sg] [20]
2
? ? 9 3 0 0 0 2 5 1
0 0 0
16 13 0 0 0 0
?
?
4 0
1
.9 ? 9 4 1 21 29 52 28 9
? 12 1
22 11 0 9 16 ll.
.9
?
13 12
1
? ? 1 0 0 1 19 33 0 31
? 4 0
1 0 0 1 3 2
?
?
7 5
2-proprio. 8-proprio. 4-visc. only 5-vise. only 46-vise. only 4-proprio. 12-visc. only
9-visc. only 2-proprio. 8-proprio. 4-deep
6-7 -
In medial spinal cord
In deep I~rainae
In superficial iam~ae
S I T neurons
S I T neurons
SIT. and SRT neurons
STl'neurons
? = not specified. a % cony. = percentage of neurons receiving excitato~ visceral input which also -~eive excitatory somatic input. b Somatic classification. Class I neurons are excited by non-noxious cutaneous shJ,~ufi. Class 2 neurons are excited by both noxious and non-noxious cutan,~us stimuli. Class 3 neurons are excited by noxious, but not non-noxious cutaneous stimufi. O~her includes the following: proprio, neurons excited by proprioeeptive inputs but aot cutaneous inputs; deep neurons excited by mechanical stimulation of ~abca~.~neous structures but not by cutaneous stimulation; inhibited neurons with no excitatory somatic input but inhibition of spontaneous activity by somatic stimuli; .rod vise. only neurons with no discernible somatic input. c Abbreviations: CAO, coronary artery occlusion, GSN, greater splanchnic nerve; NRM, nucleus raphe magnus; PAGS, periaqueductal gray stimulation; PVCs, premature ventric~,'~ contractions; PVGS, hypothalamic periventrieular gray stimulation; SC-PB, subce~leus-parabrachial region; SRT, spinoreticular tract; STF, spinothalamic tr~c~, stim., stimulation. o Number of neurons in total sample (n) responding as indicated.
Lumbar
Cat
Colon ~rectum distension
Rat Primate
Testicle compression
Lumbar
Cat
Urinary bladder distension
Cat and Primate
Coronary artery occlusion
Cat Primate
186
pathetic nerve activity [e.g., 471]. Electrical stimulation of thoracic visceral nerves also has been described as producing alterations in respiration and nictitating membrane responses [4,211]. In humans, thoracic visceral nerves, including the cardiopulmonary afferent pathways [Jonnesco, Leriche, cf., 273] and the phrenic nerve [141,494], have been stimulated to produce pain. Studies in which the phrenic nerve was stimulated are of particular interest since many were attempting to address basic questions related to the referral of visceral pain. Wollard et al. [494] electrically stimulated the phrenic nerve and produced immediate ipsilatera~ shoulder pain. These investigators then extensively infiltrated the shoulder with local anesthetic and were still able to produce pain localized t,~ the shoulder, although direct stimulation of the shoulder itself produced no pain. Doran and Ratcliffe [141] repeated these findings and further demonstrated that phrenic nerve stimulation could produce shoulder pain in a patient who had undergone a resection of the supraclavicular cutaneous nerves on one side and so was completely anesthetized across the shoulder. In other patients, they demonstrated that the intensity of phrenic nerve stimulation needed to produce shoulder pain was increased following infiltration of shoulder skin with local anesthetic, suggesting that visceral and tonic somatic inputs summate. Neuronal indices. Neurons responsive to electrical stimalati,~-,,f thora(:ic visceral nerves at intensities sufficient t o ~,cti~ate AS- ~ . d / ~ r C-fibers have been characterized in the upper thoracic spinal cord [18-27,57-61,168,169,171,172,449,456, 476], medulla [53-56] and thalamus [~,500]. The afferent pathways to and localization of spinal neurons excited by the electrical stimulation of thoracic visceral nerves has not been as extensively investigated as those of abdominal visceral nerves since studies have been limited to the upper thoracic spinal segments. As is the case for neurons excited by electrical stimulation of abdominal visceral nerves, viscerosomatic convergence is a common finding for neurons excited by electrical stimulation of thoracic visceral nerves. Exceptions are reports by Foreman and associates [57,169,456] of a small number of neurons apparently receiving only visceral in-
m
5ms
Fig. 6. Visceroceptive neurons - electrical stimuli. Example of a thoracic dorsal horn neuron in a cat excited by electrical stimulation. An oscillographic record of the response to electrical stimulation of the inferior cardiac aerve (stimulation artifact indicated by arrow) is shown; the ~nvergent cutaneous re~.eprive field of tb." neuron is illustrated below; the neuron was e×cited by fight touch and pinch [192a].
put. Catane(=s receptive fields of neurons receiving thoracic visceral input are relatively large, predominantly on the thorax and forelimbs, and centered in the dermatomes where recordings were made, primarily the upper thoracic spinal cord. An illustration typical of somatic convergence on a spinal dorsal horn neuron responsive to electrical sfimulation of the inferior cardiac nerve is presented in Fig. 6. Viscerovisceral convergence with input from the esophagus [180], gallbladder [20,23] and greater splanchnic nerve [20,21,23,24] also has been noted. Other studies [18-22,25-27, 58-61,169] have concentrated on spinothalamic tract neucons that respond to cardiac input since anterolateral chordotomies lead to partial relief from visceral pain [488] and the thalamus is unquestionably important to sensory processing. It should be noted, however, that anterolateral chordotomies also affect rostral projections to medulla, pons, midbrain and medial thalamus [487] and studies of spinal neurons projecting to these
187 supraspinal sites also are important for purposes of contrast and comparison [e.g., 58,61,169]. Pelvic visceral nerves Reflex indices. The two main pelvic visceral
nerves that have been stimulated electrically in studies of visceral sensation are the hypogastric and pelvic nerves. Afferents to the thoracic and upper lumbar spinal cord travel in the hypogastric nerve and afferent~ to the sacral spinal cord travel in the pelvic nerve, although recently a sympathetic 'contamination' of the pelvic nerve arising from the sacral sympathetic chain has been noted [219]. Stimulation of either of these nerves has been demonstrated to produce nictitating membrane responses [4], cardiovascular changes [4,418], alterations in respiration [4,176,418], visceromotor responses [176,317,498] and alterations kl sympathetic outflow measured directly from sympathetic preganglionic neurons [261,419]. Neuronal indices. Neurons excited by electrical stimulation of the hypogastric and/or pelvic nerves have been identified in the spinal cord [129,132,133,307,308], the po~i~ [] 77] and tha!amus [500]. Studies by Yokota et al. [reviewed in 500] of neurons in the shell region of the ventroposte:rolateral nucleus (VPL) of the thalamus deserve special notice; they compared the somatotopic representation of the convergent cutaneous inputs and the thalamic: location of neurons recei,~ing excitatory inpu~ from the hypogastnc, greater splanchnic and inferior cardiac nerves. Input from the inferior cardiac nerve converged on neurons located at the medial aspects of the shell region of VPL. Input from the hypogastric nerve was located in the lateral aspects of VPL and input from the greater splanchnic nerve was located between these two inputs, with many neurons excited by stimulation of the greater splanchnic nerve and also stimulation of one of the other two nerves. Convergent cutanecu~ receptive field~ of these thalamic neurons were similar to w~at is observed in the spinal cord: neurons with input from the inferior cardiac nerve typically had receptive fields in the upper limbs and thorax; neurons with input from the greater splanchnic nerve typically had thoracic and abdoram'~l receptive fields; and neurons with input from the hypogastric nerve typically had
lower abdominal and hind limb receptive fields. Similar convergence of cutaneous receptive fields with hypogastric or pelvic nerve input was noted by McMahon and Morfison [307,308] in spinal units that they considered to be local intemeurons in the sacral spinal cord and other units with ascending projections to the thoracic spinal cord or br~dn-stem. Modulation of responses to nerve stimulation
Studies on the modulation of responses to electrical stimulation of visceral nerves have been predominantly electrophysiological (e.g., individual neuronal responses were measured directly or grouped neuronal responses were measured as motor nerve evoked potentials or as alterations in the galvanic skin response, representative of increased sympathetic outflow). Sonoda et al. [433] demonstrated that potentials in the intercostal nerves evoked by greater splanchnic nerve stimulation (the viscerointercostal reflex) and a galvanic skin response in the forepaw of the cat to the same stimulus were both inhibited by electrical stimulation in the midbrain periaqueductal gray (PAG) and adjacent structures. Inhibition of the viscerointercostal reflex by stimulation in the PAG was abolished by bilateral lesions of the dorsolateral funiculus. The viscerointercostal reflex also was inhibited in a dose-dependent, naloxone-reversible fashion by the systemic administration of morphine (1-10 mg/kg). By utilizing graded stimulation of the greater splanchnic nerve, these investigators were able to demonstrate that both electrical stimulation in the PAG and morphine modulated the stimulus-response function relating the intensity of nerve stimulation to the amplitude of the viscerointercostal evoked potential in the same fashion. Fukuda and Koga [178] performed similar studies by stimulating rectal and vesical afferent nerves and found similar results. Spinal neurons excited by the electrical stimulation of visceral afferents have been demonstrated to be subject to tonic descending inhibition [88,94,95,450] or inhibition produced by the electrical or chemical activation of central nervous system sites thought to play a role in antinociceprive m~h~ufisms (e.g., the dorsolate:ral funiculus of the spinal cord [88], the nucleus raphe magnus and
188
adjacent regions in the ventromedial medulla [22,94,95,100,214,451], the periventricular gray of the hypothalamus [27], the PAG in the midbrain [99] a n d the subceruleus-parabrachial region of the dorsolateral pons [68]). In all of these studies, activation of the descending systems led to an inteasity-dependent inhibition of spontaneous unit activity (ff ~ny) a n d / o r unit act:.vity in response to visceral nerve stimulation. In these studies, Cfiber-related activity was relatively more inhibited than A-fiber-related activity wh.en tested, although this may be an artifact of the lower rate of C-fiber firing. Vagal nerve stimulation has also been demonstrated to produce an inhibition of spinal neurons excited by visceral nerv~ stimulation [1820,26,456], although some spinal neurons were noted to be excited by vagal nerve stimulation. Exceptions to descending inhibition have been noted by Cervero and associates [88,94,95,450,451] who characterized spinal neurons that were e x cited by descending influences. The application of a cold block to the cervical or upper thoracic spinal cord led to the attenuation or abolition of excitatory responses to stimulation of the greater splanclmic nerves, suggesting the existence of an excitatory spinobulbospinal loop. In a subgroup of these same neurons, electrical stimulation in the ventromedial medulla produced excitatory responses followed by a period of inhibition [94,95,4:il]; injections of the excitatory substance DL-homocysteic acid into these same brain-stem sites only produced inhibition, tlence, fibers of passage in the ventromedial medulla arising from an unknown location were likely responsible for the descending excitation [451]. These fibers may likely be components of the spinobulbospinal mechanisms of excitation noted previously by Pavlasek and Duda [372]. Segmental inhibitory effects due to repeated electrical stimulation of either the visceral nerve itself or same segmental somatic nerves also have been noted to modify neuronal responses to visceral nerve stimulation [385,421,422,451]. That is, following initial stimulation of the splanchnic nerve or conditioning stimulation of a somatic nerve, spinal unit responses to stimulation of the splanchnic nerve were reduced in magnitude for 150 msec-1 sec. Seizer and Spencer [422] pre-
sented evidence that the mechanism for this phenomenon is primary afferent depolarization. In general, it is apparent that neurons excited by the electrical stimulation of visceral nerves appear to be subject to the same segmental and suprasegmental modulatory influences as nociceptive neurons excited by the electrical stimulation of somatic nerves. Since most of the neurons examined in the above studies had both vis~ral and somatic inputs, this should not be suprising. To the best of our knowledge, no studies have attempted to examine the effects of analgesic drugs (e.g., morphine) on spinal neurons excited by the electrical stimulation of visceral nerves. S u m m a r y - electrical stimulation
Electrical stimulation of visceral nerves is a reliable reproducible stimulus, the intensity and duration of which can be easily controlled. Electrical stimulation of abdominal visceral nerves and organs has been demonstrated to produce reports of pain in humans and vigorous pseudoaffective responses in animals. Electrical stimulation of the mucosa of the gut also has been demonstrated to alter behavior is rats, suggesting the aversive nature of the stimulus. Numerous spinal neurons have been characterized that are excited by electrical stimulation of visceral nerves and, in general, many would be classified as nociceptive based on their convergent cutaneous receptive fields. Some excitatory responses to the electrical stimulation of visceral nerves have been demonstrated to be inhibited by presumably antinociceptive manipulations. The biggest drawback to the use of electrical stimulation of visceral nerves is that it is neither a natural stimulus nor is it modality- or organspecific. Further, alterations in the characteristics of primary afferents within the viscera due to pathological processes, which appear clinically to be important to an understanding of visceral pain, are not amenable to study using only electrical stimulation as a stimulus. M~c~a~ical stimuli as noxio~ visceral stimuli
As reviewed by Lewis [273], mechanical stimuli such as traction of the mesentery, distension of
189
hollow organs, stretch of serosal tissues and compression of some organs such as the testes produce pain in humans. These are stimuli which also produce pain in pathological states such as obstruction of the common bile duct or gut. Lewis also noted that distension of hollow organs such as the gut was most painful when long continuous segments of gut were simultaneously distended. High pressures within small segments were not as efficacious in producing pain. As discussed by Lewis [273], numerous clinicians such as Lennander, Bier, Capps, MacKee~e and Wilms have noted the relative ineffectiveness of pressure, cutting, scratching or pinching of either healthy or inflamed visceral structures for the production of pain in humans. The parietal pleura and peritoneum covering the inner surfaces of the chest and abdominal walls are well accepted as being sensitive to tension as is adjacent mesentery, but the visceral pleura, peritoneum and visceral parenchyma are often insensitive to probing. Pain often is elicited using these same stimuli when the viscera are inflamed. An example is a case report by Wolf [cf., 203] of a patient with a gastrostomy in whom the mucosa of the stomach could be observed and manipulated directly. When the gastric, mucosa of this patient became hyperemic and engorged, the ~hreshold for pain was reduced to the point that pressure or pinching of the mucosa became profoundly painful whereas at other times, when the muco~a appeared normal., these stimuli were not painful at all. Similarly, Kinsella [241] demonstrated ~.hat pressure applied to an isolated inflamed appendix readily produced pain. Because distension of hollow organs is a natural stimulus which produces pain in humans, numerous studies have examined sensations evoked by mechanical stimulation of hollow organs. These include the gastrointestinal tract, the urinary tract, the vagina/uterus and the biliary tree/gallbladder following surgical manipulations. As the gastrointestinal tract is easily reached via natural orifices, experimental investigations of the gut outnumber those performed in all other viscera combined and will be considered in some detail. Hence, to facilitate reading, the studies of visceral nociception involving the gut
are listed under the subheadings of human studies, reflex and behavioral studies, neuronal studies and studies of modulation. Discussions of other organ groups will not be similarly subdivided, but the same format will be followed. Gastrointestinal gract Human studies. Since the time of Hertz [209],
numerous clinical studies in humans have distended the gut to produce pain. Two early investigators, Payne and Poulton [373], began their study of visceral pain by examining patients with intermittent pain of presumed gastrointestinal origin. Using motility-monitoring balloons, they demonstrated that specific movements of the esophagus, stomach, duodenum and jejunum were associated with patient reports of pain [see also, 213]. Payne and Poulton [374,375] then repeated studies by Hertz [209] and artificially distended their own esophaguses, correlating sensation with the volume/pressure of distension. They described their pain as 'continuous and burning' at low volumes/pressures and 'gripping' at the greatest volumes/pressures of distension. Pain was referred from the area of the suprasternal notch to the xiphoid process and sometimes to the costal angle, with radiation through to the angle of the left scapula. Pain was experienced with spontaneous conh-actions of the esophagus on non-compressible balloons and with the maintenance of a minimal constant pressure within a distending balloon (constant volume distension produced contractions and pressure waves witlfin the balloon; pain was correlated not with peak pressures within the balloon, but with the maintenance of a minimal 'diastolic' pressure of 30 cm water). Painful distensions produced alterations in the patte .,'n of breathing and, if the experimental protocol wa~ prolonged, the experimenters began to experience cutaneous hyperesthesia in the skin over the sternum. Polland and Bloomfield [384] confirmed the findings of Payne and Poulton by distending the esophaguses of 39 volunteers. A quote from their stu0y is illuminating; 'The most striking feature of the referred sensations was the inability of the patient as a rule tc, Cescribe them exactly. On the whole, they seemed o fall under the heading of
190
p a i n . . . l t was difficult to define the referred sensations in relation to body surface and while the subjects pointed to a fairly definite location in front or in back, the pain was usually described as being inside rather than superficial.' Descriptors of the pain included 'burning,' 'a severe dull ache,' 'something sharp,' 'a kind of suffocating pain, like one wanted to take a breath and couldn't' and 'a pressure, no pain, but it hurts.' In addition to pain referred to midsternal and epigastric regions, pain was also 'localized' over the entire anterior chest wall, in the back and occasionally in the neck or face. These investigators also examined volume distension of the stomach, duodenum and colon [63]. Descriptors of the pain originating from the stomach were similar to those ~sted above, but the pain was localized primarily in the epigastric and periumbilical regions. The ~olume threshold for pain sensation varied markedly front 400 to 1500 ml. Inflation of a balloon in the duodenum produced a more intense pain and sites of referral were predominantly epigastric and periumbilical. Duodenal pain was likened to esophageal pain, but was less like stomach pain in patients tested i,l all sites. Distension of the descending and sigmoid colon produced diffuse abdominal pain to left sided pain described as 'ccamps,' 'like gas pain' and ':~r~'ssurc pain.' An interesting study by Weiss and Davis [477] also used balloon distension of the esophagus as a stimulus. These investigators infiltrated the skin with local anesthetic over sites of referred pain from balloon distension and reported that the referred pain shifted from the original site to an adjacent site, only to return to the original site foUowing cessation of the local anesthesia. These investigators repor~.ed that pain was never abolished by the local anesthetic, but that the imensity was reduced and localization of the pain was affected. Chapman and Jones [102] were the first to determine pressure thresholds for painful sensations utilizing balloon distension of the esophagus in 29 volunteers. These investigators sl,~wly increased the pressure within the distending balloon until volunteers reported a ~ensation of substernal fullness and continued until the volunteers reported that the sensation had become painful, described as ,~. sense of 'oppression,' 'heartburn,'
'a cramp ache' or 'a sharp stab.' Thresholds for the sensation of substernal fullness varied from 15 to 90 cm water (most < 35 cm water) and were highly correlated with cutaneous thermal pain thresholds in the same volunteers. However, volunteers were unable to define a precise pressure when the substernal fullness acquired a definite hurting quality as the sensations were a continuum. These investigators were concerned that tonicity of the esophageal wall affected their pressure thresholds and administered atropine sulfate to 4 individuals. Atropine produced a 307o reduction in the resting tone of the esophagus (increased volume of distension), but did not change the visceral sensory pressure threshold. Moving down the alimentary tract, Bentley and Smithwick [48] distended the jejunum of 6 healthy individuals, 3 of which subsequently underwent partial sympathecto~es for hypertension. Pain due to jejunal distension was described as 'like intestinal colic but more severe and nauseating than any colic vet experienced,' 'sickening' and like a "stomach ache.' Pain was roughly localized co the epigastric region at low volumes of distension ai:d spread to include the entire upper abdomen at greater volumes of distension. After partial sympathectomies/sglanchnic nerve division, pain was either abolished or iateralized to one side whereas previously it had been a midline sensation. Similar studies and results were reported by Ray and Neill [391]. Goligher and Hughes [189] examined the sensibility of the sigmoid colon and rectum using volume distension with pressure measurements. A notable finding was that the sensation of pain was related to the pressure within the balloon rather than the volume; rapid balloon inflation with a fixed volume of air produced pain which waned as the intestinal wall relaxed and the intraluminal pressure lessened. Descriptors of the evoked sensations varied from 'definite pain like a colic but continuous' to the sensation of pressure. Goligher and Hughes made a distinction between colonic sensation and rectal sensation, the former being 'pain' carried by afferents in the sympathetic nerves and the latter 'fullness' carried by afferents in the pelvic nerve. However, they were unable to localize this pain specifically to the colon or rectum.
191
Lipkin and Sleisinger [278] were the first investigators to use controlled, constant pressure stimuli in studies of sensation from ~he gut. Using balloons to distend the esophagus, ileum or colon phasically in 51 patients, they demonstrated that the latency from the onset of the phasic stimulus to patient reports of pain was directly related to the intensity of the distending stimulas. At distending pressure~ ~,reater than 50-60 mm Hg, reports Gf pain were immediate in all 3 organ sites and pain was the only sensation. Sites of referred pain and descriptors of this pain were similar to those described above. At lesser distending pressures, the stimulus was not reported as painful for up to I min following the onset of distension and was preceded by a sensation of pressure over a large abdominal or thoracic area. This pain was
described as an aching pain which arose within a smaller area of the total area to which the preceding pressure sensation had been referred. The minimal intraluminal pressure to produce painful sensations from the esophagus was 39-47 mm Hg, from the ileum 44-59 mm Hg and from the colon 40-50 mm Hg. It should be noted that the reported values of distending pressure were 'corrected' values which the investigators calculated from measured values by subtracting the pressure necessary to overcome the elasticity of the distending balloon. Measurements made in the same patients on 3 different days established that responses of these p_a.tie~ts to the same distending stimulus (sigmoid colon, 74 mm Hg) were reproducible and reliable. Using this same stimulus, these investigators also documented that the re-
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Fig. 7. Psychophysiological experiments. Balloon distension of a 25 cm segment of sigmoid colon (60 nun Hg, 30 sec, constant pressure control) led to achy pair= localized to the lower abdomen, perineum and upper lumbar back. The area illustrated on the cartoon indicates where pressure ~:as sensed during distension; the completely filled area indicates where both pain and pressure were sensed. Colonic distension led to an increase in blood pressure (right - top) and a decrease in heart rate (right - middle). Subjectively, the intensity of unpleasant sensations increased during sustained distension (right - bottom). [Ness, Metcalf and Gebhalt, unpublisi~ed.]
i92
sponses of patients to this consistent stimulus fc,Uowed a norm~ distribution. Other studies [41,46,79,101,149,155,230,236, 240,251,262,263,299,32%332,395,397-399,446,484] have verified findings of these investigators and have consistently demonstrated that pain produced by distension of the gut is very similar, if not identical, in intensity, quality and location to pathologically experienced pain arising from the gut. An illustration representative of this literature is given in Fig. 7. These studies, in the aggregate, suggest that alterations in sensation (e.g., visceral hyperalgesia) may be a pathological condition which r e s ~ s in abnormal gut function or that local pathological conditions produce abnormal gut h~.nction which leads to an increase in pain. Most of these studies used volume distension as a srmulus, w~ch fails to differentiate pathological changes in compliance from hyperresponsivity or hypersensitivity of the bowel, and hence at present no conciusive statement can be made regarding hyperalgesia of the gut. In summary, human psychophysiological experiments related to pain produced by distension of the gastrointestinal tract reveal that pain is produced when the intraluminal pressure of this hollow org~,r~ is maintained above a certain pressure threshold. Pressure thresholds Are ~:'eliable measures of pain thresholds within individuals (~epeated measures) ~nd between different indivi,tua!s (threshold pressures are normally distributed), whereas volumes of distension necessary to evoke reports of p~in were neither reliable within the same subject nor between subjects. The descriptors of experimental pain evoked from the gut were similar to the descriptors of pathological pain, but varied widely. Initial sensationn to low volumes/pressures of distension were described as non-pai~ful pressure which became painful as the intraluminal pressure increased or the stirnuius was maintained. Studies ha humans did not report whether sensations or thresholds changed with repeated distensions nor did they report wheiher any physiological changes (e.g., cardiovasc~flar responses) consistently occurred in response to distension. Reflex and behavioral studies. Mechanical stimulation (disten:;ion oa ce~apression) of the gut
also has been used widely in non-human animal investigations of visceral nociception. In the eat, rat, rabbit and dog, mechanical stimulation of the esophagus [206,415], stomach [146,151,206,283, 284,302,310,317,387,420]~ small intestine [34, 104,111,112,117,146,147,191a,206,231,269,274,310, 317,388,420,467] and large intestine/rectum [115, 123,175,206,227,285,342,454,470] have been demonstrated to produce nictitating membrane/pupillary responses [147,206,310,470] cardiovascula~ responses [104,123,146,147,151,175,231,269,274, 283,284,302,342,387,415,454,470], changes in respiration [34,117,175,I91a,388,415,420] and visceromotor responses consisting of the contraction of abdominal a n d / o r hind limb muscles [34,111, 112,115,123,146,147,175,227,274,288,317,342,467]. Stimulus-response functions relating thz intensity of the distending pressure and the magmtude of cardiovascular changes have been noted [151,284,302,342,470]. Both the magui'ude and qu.,dity of the cardiovascular changes reported differ among preparations, species and investigators, some reporting increases in blood pressure/heart rate, others reporting decreases. We [342] investigated the influence of anesthesia/preparation on cardiovascular responses to coloreetal distension in rats arid found that the response to colorectal distension in unanesthetized intact rats was a brisk presser response with tachycardia while in deeply anesthetized, acutely prepared, rats it was a depressor response with bradycardia (Fig. 8). Whether the differences in responses to distension were due to direct effects of the anesthetics or secondarily to physiological alterations such as depth of respiration is unknown. Regardless, such data clearly indicate that the preparation can significantly influence the responses measured in the rat and likely other species as well. Pseudoaffective responses to distension of the gut are blocked by splemchnectomy [e.g., 283] and selective rhizotomy at various thoracic and uppe~ lumbar segments [206,310], except for responses to distension of the 6esccnding colon and/or rectum [206]. In the cat, visceromotor and cardiovascular responses to distension of the gut could be elicited ir decerebrate preparations [e.g., 146] and in spinalized preparations by some investigators [e.g., 14619 but not by others [e.g., 274]. In the rat,
193 mmHg
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markedly reduced blood flows when mtraluminal pressures approach intensities that would produce pare m immams. The iochca~ic ~:hanges produced secondary to this reduced blood flow potentially could be responsible for pain originating from the gut or could be a sensitizing factor responsible for the initial increases in magnitude of neuronal, cardiovascular and visceromotor responses to
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cardiovascular and visceromotor responses to colorectal distension are vigorous in the decerebrate state, but th,: visceromotor response is apparently abolished and the cardiovascular responses markedly attenuated by spinal transection [342]. Using pseudoaffective responses as a measure of afferent input:, Downman et al. [147] were able to produce responses with selective compression of the mucosa, the musculans and the serosa of the small intestine, implicating all 3 sites as sources of pain due to distension. Other studies have examined the effects of distension on blood flow in the gut [65,201,202,360] and have o~served
Fig. 9. Behavior. Examples of alterations in behavior produced by a s4sceral stimulus. Using a conditioned avoidance paradigm in which rats were placed on a 15 x 15 x 10 cm platform in an open field mad the latency to step down from the platform measured, rats (n = 5/group) received colorectal distension (CRD, 20-80 mm Hg, 20 sec) when both forepaws were placed on the floor whereas control rats; (n = 10) did not. When intrahinunal pressures of CRD were 40 or 80 nun Hg, all rats avoided CRD by remaining oil the platform until cutoff (120 sec). At intraluminal pressures of 30 mm Hg or less, experimental rats did not behave diffe:~:ntly than control rats. Data are expressed as the mean step-down latency (A) and percentage of rats reaching criterion (B; criterion--stepdov, a latency > 120 sec for 2 consecutive trials). Note: lines have been separated slightly for clarity [Ness, Gebhart and Randich, unpublished; see 342].
194
colorectal distension observed in the rabbit [227] and rat [342,343]. One study has examined whetL¢r distension of the gut is aversive to animals [342]. Using a conditioned avoidance paradigm, colorectal distension was shown to alter/inhibit the normal step-down behavior of rats when placed on a raised platform in an open field at. an intraluminal pressure threshold for effect near 30 mm Hg (Fig. 9). Neuronal studies. Distension of the colon/ rectum has been used ,ts a visceral stimulus in studies of spinal dorsal horn neurons in cats [133,154,160,215,307,308] and rats [73,340,341, 343-346]. Fields et al. [159,160] recorded from axons traveling in the white matter of the cat spinal cord, predominantly the ventrolateral quadrant, and characterized these units as excited or inhibited in response to distension of the gut, gallbladder a n d / o r urinary bladder. They reported a b~-gh degree of viscerosomatic convergence in ascending fibers (presumably projection neurons) and descending fibers (presumably proprio~pinal or bulbospinal neurons); all neurons 'responsive' to distension (excitatory or inhibitory responses not specified) also responded to a somatic stimulus. Likewise, they noted a high degree of viscerovisceral convergence. DeGroat et al. [133] c~'aracterized sacral spinal interneurons near the parasympathetic motor nucleus and found a reciprocal relation between activity produced by urinary bladder and colonic/rectal stimulation: of 25 neurons excited by rectal stimulation, 13 were inhibited and 2 were excited by bladder distension while of 26 neurons inhibited by rectal stimulation, 17 were excited and 3 were inhibited by bladder distension. Convergence of excitatory input from the vagina and perianal region was also noted. McMahon and Morrison [307,308] no~ed somatovisceral and viscerovisceral co,vergence in recordings from 26 spinal units excited by mechanical probing or distension of the colon/ rectum in the cat; 7 of these neurons also were excited by urinary bladder distension and 6 were inhibited by the same ~tir,~ulus. Nine of the neurons excited by distension of the colon/rectum had long ascending projections to the C1 spinal segment and also encoded the intensity (pressure) of coiomc distension in a monotonic accelerating fashion.
We [340,341,34.a-346] have characterized similar neurons in the rat by quantifying the responses of > 300 neurons located in the T13-L2 and L6-$2 spinal segments to phasic pressure-controlled balloon distension of the descending colon and rectum. Based on the temporal relation between neuronal responses and the phasic distending stimulus (80 mm Hg, 20 see), 4 groups of neurons were identified. Mo~t units (73~) were excited coincident with the onset of the distending stimulus; the responses of approximately one-third of the neurons abruptly terminated coincident with termination of the distending stimulus ('abrupt' neurons) while responses in another one-third of the unit sample were sustained for 4-240 sec following termination of the distending stimulus ('sustained' neurons). The spontaneous activity of approximately one-fifth of the unit sample was inhibited by the distending stimulus and the remaining units exhibited relatively long latencies ( > 4 sec) from the onset of the distending stimulus until an excitatory response occurred. Pressure thresholds for responses extrapolated to near 0 mm Hg for 'abrupt' units and 15-20 mm Hg for 'sustained' neurons (Fig. 10). Units of all grot~ps except those with long latencies for resl:,onse were found to have long ascending projections to the brain localized to the ventrolateral quadrants. Both abrupt and sustained neurons were excited by intraarterial (abdominal aorta) administration of bradykinin, were under tonic descending inhibition and had a high degree of somatovisceral convergence with relatively large cutaneous receptive fields. Honda [215] recorded from 23 neurons located near the central canal of the sacral spinal .cord of the cat that were excited by colonic distension. Somatovisceral con~'~rg~ce (cutaneous receptive fields in the perineal region and hind limbs) was documented for 83~ of these neur~,~:s. Viscerovisceral convergence with excitatory input from the bladder was noted in 16 of the 23 neurons. Honda also labeled several of these neurons intracellularly, demonstrating patterns of dendritic arborization ranging from restriction to the area near the central canal to extension through laminae V and VII into the entire base of the dorsal horn. No distinct cell morphology was apparent for neurons excited by colonic distension. However,
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these neurons were simply classified and so the functional classifications may have been too broad to allow for definiti, on of a pattern. Recent work by Garrison et at. [180,181] has revealed the existen~ of neurons in the thoracic spinal cord encoding distension of the distal esophagus. These neurons were found to encode volume distension in a monotonic accelerating fashion. Distension of the gut also has been demonstrated to affect higher-order neurons in the medulla [e.g., 379], ports [151,1"/7], thalamus [82,85], hypothalamus [e.g., 226] and cortex [e.g., 85,116]. Of these reports, that by Carstens and Yokc~ta [82] is particularly interesting. They recorde~ from units located at the junction of thc
midbrain and posterior thalamus and tested for responses to distension of a fistulated portion of the jejunum. Of 134 units excited by splanchnic nerve stimulation, 28 also were excited by distension of the jejunum. Nine of these 28 units responded o ~ y at the onset of distension and 7 had convergent cutaneous receptive fields that responded to low threshold mechanical stimuli; 5 of the receptive fields were relatively small, consisting of 1 limb or less. The other 19 units gave responses which lasted through all or most of the period of distension, 6 outlasting the stimulus. All 19 of these units had large receptive fields, consisting of 2 or more limbs and often the entire body, and 9 of these responded best to stimuli such as pinch or noxious heathlg of the skin. Although not
~96
quantified, the responses of these 19 units appeared to be graded in response to graded distension. Elam et al. [151] also have demonstrated graded responses of locus ceruleus neurons directly related to the magnitude of d~tension of the distal colon and stomach. Modulation. Two studies in humans have attempted to modulate responses to experimental distension of the gut. In one of these, Woolf et al. [492] inflated a duodenal balloon and demonstrated that the parenteral administration of morphine sulfate led to an increase in pain threshold and pain relief. Payne and Poulton [375] reduced the subjective sensation of pain due to distension of an esophageal balloon by utilizing a amstard pack applied to the anterior chest wall, thereby producing 'counter-irritation' - - the masking of one pain by another. Several investigators have utilized pseudoaffective responses to distension of the gut for pharmacological studies of visceral pain, some in anesthetized animals, others in unanesthetized physiologically intact animals. Lembeck and Skofitsch [269] and Clark and Smith [104] reported that depressor responses to distension of the proximal jejunum in deeply anesthetized (pentobarbitai, urethane) rats were inhibited by opioids and by neonatal pretreatmcnt, with capsaicin. Unfortunately, unreliable responses to distension app~wently limited the use of this model of visceral pain: only 60% of the rats had depressor responses in one study [269] and 72% in the other [104] and repeated measures in the same rat led to a reduced response [269]. Similar depressor responses tv dis:c~ :sion of the colon and rectum of deeply anes~nctized rats have been noted [342] (Fig. 8). In awake, unanesthetized rats, MacKenzie-Taylor et al. [288] reported that systemically administered opioids increased the volume of coIonic distension needed to evoke a visceromotor response with a selectivity of opioid receptor subtypes. Coombs and associates [111,112,113a], utihzmg a volume-distended duodenal balloon to evoke a visceromotor response (writhing) in rats, re:poll
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opioids and the analgetic c~2-adrenoceptor e~gop.ist clonidine produce dose-dependent inhibition of this response. Unique to this model, chronic surgi-
cal implantation of the balloon prodm.c., local (duodenal) inflammation [111]. Reflex responses to pressure-controlled colorectal distension in rats have been demonstrated to be reliable and reproducible both between and within animals and are dose-dependently inhibited by opioids given intravenously [342] or intrathecally [342], by intrathecal a2-adrenoceptor agonists [123,342], by electrical stimulation in the PAG of the midbrain or rostal ventromedial medulla [Ness and Gebhart, unpublished] and by presentation of conditioning noxious stimuli in distant cutaneou3 receptive fields [344], which may be related to the counterirritatior~ of visceral pain in humans noted above [375]. Examples of the modulation of responses to colorectal distension in the rat are given in Fig. 11. Recent work by Jensen et ai. [227] demonstrates similar reproducibility and reliability of the visceromotor responses to pressure-controlled coionic distension in rabbits and inhibition of the responses by morphine. Modulation of neuronal responses to distension of the gut also have been examined. Morphine and clonidi,c produce dose-dependent, antagonist-reversible inhibition of spinal neurons excited by colorectal distension [346]. Electrical stimulation in the PAG or rostroventromedial medulla produces intensity-dependent inhibition of neurons excited by eolorectal distension, an effect also produced by chemical activation of cell bodies by glutamate in the same supraspinal sites [341]. Conditioning noxious stimuli applied to distant cutaneous receptive fields also modulates the activity of spinal neurons excited by colorectal distension [344].
Urinary bladder There is limited e.xperimental information about pain originating from the urinary bladder, but a wealth of clinicai data. Cystic calculi or rapid filling of the urinary bladder during cystoscopy commonly produces pain that is poorly localized to the lower back, suprapubic and perincal regions. This pain has been studied clinically during cystometrograms where a volume of fluid is infused via a catheter into th,: bladder; intravesical volumes, intravesical pressures and subjective sensations are recorded. Typically, the cystometro-
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Fig. 11. Modulation of visceroeeptive neurons. A: data from 3 thoracolumbar spinal dorsal horn neurons in the rat excited by coloreetal distension (CRD; 80 mm Hg, 20 see). The control neuron gave consistent responses during CRD (repeated every 4 min) for a period of 2 h, whereas application of a 25% solution of turpentine solution to the colorectal mucosa (at arrow) led to increased responses in another neuron. In a third neuron, the intravenous administration of morphine sulfate (mor) led to a dose-dependent naloxone (nal)-reversible inhibition of responses during CRD. B: stimulus-response funetimts (SRFs) of the same units in A, characterizing neuronal responses (total no. impulses minus spontaneous activity) t,., graded stimuli. Responses at all intensities of CRD were enhanced following turpentine treatment (top) while responses of the control unit were the same at the begim',h-,g ~a,d end of the experiment (center). Morphine (bottom) attenuated responses during CRD. Filled symbols are SRFs at time 'zero'; open symbols are SRFs at times indicated by * ha A [346a].
gram has been employed to study compliance or spasticity of the bladder and not sensatio~lo Precise, controlled stimuli typically have not been used in studies of human urinary bladder sensation. A continuum of sensation during distension of the bladder has been reported; the initial sensation of ful~xless becomes compounded by a sense of urgency and urethral sensations until frank pain with profound urgency is finally expe-
rienced [134,33~]. Reports of pain appear to be directly related to the pressure of the fluid within the bladder and not to the volume (although volurae is obviously related to pressure L'~ a c!osed viscus), since pain waxes and wanes with isovolumetric, contractions of the bladder. Simple sympatheetomy does not abolish urinary bladder sensation, but sympathectomy in addition to rhizotomy at $2-4 or pelvic nerve section does
198
lead to a loss of sensation produced by distension of the bladder [267]. Anterolateral chordotomies abolish both the sensation of the need to micturate and pain from :he bladder during distension [338]. Distension of the bladder in humans often has been noted to produce cardiovascular and other autonomic responses [120,193,495]. Most animal studies utilizing mechanical stimulation of the urinary bladder, predominantly distension, have been concerned with micturition reflexes or interactions with other autonomic functions, such as defecation reflexes [e.g., 133,304]. However, some studies do contain information related to pseudoaffective responses and responses of neurons which couid potentially be nociceptive. Distension of the bladder produces cardiovascular changes in both intact and spinalized animals [151;333,419,426,452-454,470,472], changes in respiration [154,175,314,333,4!8], visceromotor responses [154,175,314], responses of the nictitating membrane [470], and cha'ages in circulating catecholamines and cortisol [426]. The cardiovascular responses to distension of the bladder were directly related to the pressure within the bladder and only indirectly related to volumes of distension. Infusion of the local anesthetic procaine into the lumen of the urinary bladder blocked cardiovascular responses to distension [472], as did complete splanchnectomy [333]; cardiovascular responses were attenuated by cutting either the hypogastric or pelvic nerves, but abolished only when both nerves were cut [453]. Numerous studies have examined the effects of opioids on the micturition reflex [e.g., 148], but to the best of our knowledge none have examined the effects of opioids on pseudoaffective responses to urinary bladder distension. Several studies have recorded from spinal [132,133,158,159,215,232,307,308,319] and pontine [e.g., 151,177] neurons responsive to distension of the urinary bladder. Spinal neurons excited by bladder distension were located throughout the dorsal horn, in the area near the central canal and in the region of the parasympathetic (sacral) and sympathetic (thoracic) nuclei; some of these neurons sent projections rostrally through the ventrolateral quadrants of the spinal cord. In addition to neurons excited by urinary bladder distension,
some spinal neurons are inhibited. In several studies, graded distension of the bladder produced graded increases or decreases in neuronal activity in apparent direct relation to the intraluminal pressure and only indirectly with the volume of distension [132,133,151,307,308,319]. Pressure thresholds for the excitation or inhibition of specific neuronal types has not been undertaken quantitatively. However, an interesting finding by DeGroat et at. [133], who examined sacral interneurons near the parasympathetic motor nucleus, was the existence of at least two populations of neurons excited by distension of the urinaqr bladder: one group encoded the intensity of pressure-controlled bladder distension in a hnear fashion both above and below the pressure threshold necessary to evoke micturition and a second population of neurons exhibited a near maximal firing rate when the micturition threshold had been exceeded. The responses of this second population of neurons were similar to responses of preganglionic parasympathetic neurons to the same stimulus [] 32]. One interpretation of these data would suggest that the latter group of neurons were exclusively involved in non-nociceptive autonomic reflexes whereas the former group of neurons, or a subset thereof, were likely involved in nociceptive processing. Honda [215] recorded from 48 neurons that were located near the central canal of the sacral spinal cord in the cat excited by distension of the urinary bladder. A high degree of somatovisceral convergence was noted (81%) with convergent cutaneous receptive fields in the perineum and hind limbs. Viscerovisceral convergence also was common; excitatory input from the distal colon was found in 13 of these neurons. Honda filled intracellularly several neurons receiving excitatory input from the urinary bladder. As noted above for cells labeled by Honda that responded to colonic distension, no unique cell morphology was apparent for neurons r~ceiving bladder input, although the characterization of the neurons was simple and the sample small so that patterns may yet become apparent. A consistent finding in studies of spinal neurons excited by urinary bladder distension is the existence of convergent cutaneous receptive fields
199
in a high percentage of the neurons tested. Milne et al. [319] found that of 36 primate spinothalamic tract neurons excited by distension of the urinary bladder, 100% of those neurons located at the thoracolumbar junction (n = 19) and 76% of those located in the sacral spinal cord (n--17) had convergent cutaneous receptive fields; the other 4 neurons located in the sacral cord had 'deep' (subcutaneous) convergent receptive fields. Other studies cited above of neurons excited by distension of the urinary bladder have not demonstrated a 100% convergence between visceral and somatic excitatory inputs, but have not examined spinothalamic tract neurons specifically. Inhibitory cutaneous receptive fields of spinal neurons included segmental non-noxious inputs and segmental and non-segmental noxious inputs. Convergence of excitatory a n d / o r inhibitory inputs from other viscera such as the esophagus [158], testis [319], gallbladder [158,159], colon/rectum [132,133,215,307,308] and vagina [132,133,177] also was a common finding. Studies by Fields et al. [158,159] revealed gross temporal correlations of neuronal activity with changes in blood pressure and consistently found that responses (excitatory, inhibitory) of neurons with axons in the ventrolateral quadrants of the cervical spinal cord preceded the changes in blood pressure. No attempts were made to link the intensity of bladder distension with the threshold for activation of cardiovascular responses. Cervero and lggo [93] utilized distension of the bladder as a conditioning stimulus and reported that it had no effect on spinocervical tract neurons in the cat. Cadden and Morrison [73] recorded from dorsal horn neurons in the lumbar enlargement of the rat and demonstrated that distension of the bladder led to the inhibition of class 2 cutaneous neurons. Similar work by Brennan e~ al. [69] demonstrated that bladder distension at~o had an inhibitory effect on primate spinothalaml ~ tract neurons in the T2-T5 spinal segments. These studies suggest that bladder distension activates mechanisms related to the phenomena of counter-irritation. Kidney and ureters Renal colic is thought to be secondary to ureteral ob,struction and subsequent distension of
the ureter and renal pelvis since t.his pain occurs clinically with kidney stones large enough to produce obstruction. Experimental work in humans [Lennander, cf., 273,391,396] has established that probing the pelvis of the kidney or distension of the ureters and pelvis produces pain localized to the flank and lower half of the abdomen of the stimulated side. Risholm [396] determined that an intraluminal pressure threshold of 29-79 cm H20 was necessary for the production of pain due to distension of the ureter and kidney pelvis and reported that sympathectomy abolished the pain. Ray and Neill [391] also reported that sympathectomy abolished pain due so ureteral distension or traction on the ureters or kidney pelvis/pedicle. They also noted that electrical stimulation or pressure applied to the renal capsule not bordering the renal pelvis was non-painful. Woodworth and Sherrington [490] were the first investigators to demonstrate that mechanical manipulation of the ureter could produce pseudoaffeetive responses in dogs. Their studies were most notable, however, for the lack of response to ureteral distension following hemisection of the contralateral spinal cord. Brasch and Zetler [67] developed an animal model of renal colic by cannulating the ureters of pentobarbital-anest.hetized rats and distending the renal pelvis to pressures of 80 mm Hg, producing reliable depressor responses that were attenuated/abolished by morphine (0.5-1 mg/kg; reversed by naloxone) or the decapeptide cerulein. Cardiovascular responses to ureteral distension, manipulation of the kidney and renal venous occlusion also have been documented by other investigators [e.g., 16,185,462], but by virtue of their use of selective analgesic drugs to modulate the responses, Brasch and Zetler [67] were the first to make a good case for these changes being representative of a visceral pain. Visceromotor responses also can be evoked by mechanical stimulation (pinch, poke) of the kidney [317]. Kostreva et al. [2491 reported that cardiovascular changes occur with renal vein occlusion, a finding confirmed aad extended by Ammons v,~o reported that ureteral or renal venous occlusion excited roughly half of 64 spinoreticular neurons in the cat [i6] and 38 spinothalamic neurons in the
200 primate [17c]; all spinal units in both studies were excited by renal nerve stimulation. All neurons excited by venous occlusion also were excited by meteral occlusion when tested for responses to both stimuli [16]. However, some neurons were excited only by ureteral occlusion and not venous occlusion; 100% of these neurons had somatic convergent receptive fields, most of which were class 3 in character [16].
Biliary system Pain arises from the gallbladder and biliary tract with obstruction of the cystic or common bile ducts, which elevates pressure (generally 35-45 mm Hg) within the biliary system [118,350]. Several investigators [391,501,502] were able to reproduce this pain by distending gallbladders in humans under local anesthesia and/or lightened general anesthesia or by distending a fistulated gallbladder via a cholecystostomy [359]. In these studies, distension or traction on the gallbladder led to deep, epigastric pain, inspiratory distress and vomiting as well as cardiovascular responses. A T-tube cannulating the biliary tract used to be commonly employed following cholecystectomy tor surgical drainage; this allowed ready access to the biliary system for researchers interested in studying sensation produced by distension of this system. Pain due to distension of the biliary system was reported to be identical to pain experienced pathologically [101,140] and was directly related to intraluminal pressure of the biliary tract [300] since pain was associated with pressure waves within the biliary system and was referred to the right upper quadrant of the abdomen, right scapula and right shoulder. Ravidin et al [390] reported that in patients with underlying coronary artery disease, distension of the common bile duct led also to precordial and upper li~(~ referral of pain. Distension of the biliary tract also produces rigidity of the abdominal wall, ins!firatory distress, nausea, vomiting and belching ['266] and cardiovascular change; 152,212,299,3~,2]. Spontaneous spasm of the spai ~cter of Oddi or that induced by morptfine leads to increases in pressure in the biliary system and ~ubsequcnt increases in pare sensation [266~3~0]. The inhalation of amyl nitrate l~roduces a ~ehxation within the bilia~ system ,
and a subsequent drop in intraluminal pressure and pain [300]. Ray and Neill [391] and others [483] have demonstrated that experimental pain due to stimulation of the gallbladder is blocked by bilateral splanchnectomy. Gaensler [179] quantitatively examined the relation between biliary intraluminal pressure and pain sensation in studies in 40 patients. Pain thresholds were documented to be reproducible and reliable within the same subjects; 17 different determinations over a period of 12 h revealed httle variability. By performing repeated measures on the same patients with T-tubes in place, Gaensler was able to demonstrate that pain thresholds (measured as intraluminal pressure) increased as inflammation within the biliary tract decreased. Pain thresholds were as low as 9 cm H,O (mean~ 43 cm H20 ) immediately following surgery, whereas pain thresholds varied from 20 to 80 cm H20 (mean, 54 cm H20) following recovery. Gaensler also demonstrated that administration of morphine and other opiates, but not aspirin, acutely increased the pressure threshold necessary to produce pain due to distension of the bihary system. Animal studies of pseudoaffective reflexes arising from distension of the biliary system were first reported by Woodworth and Sherrington [490]; they noted that injection of water into the bile duct of a dog produced facial reactiops and pressor responses of 14-36 mm Hg. Cervero reexamined these pressor responses in cats [86] and further demonstrated similar pressor responses to gallbladder distension in the r. . . . . ,n-. I,, sure thresholds for the pressor response observed by Cervero were 20-25 mm Hg and responses were graded with the distending pressure. In Cervero's study of the ferret, he demonstrated that biliary pressures of only 5-7 mm Hg produced relaxation of the sphincter of Oddi. Section of both greater splanchnic nerves was necessary to abolish the cardiovascular responses to distension of the gallbladder, although the effect of right splanchnic nerve section was predominant. Similar results incats had been noted previously by Newnian t.~ll Wind determined that the adrenal [~ands were responsible for much of the pressor response. Ammons and Foreman [23] also e x a ~ n e d pressor r~t=
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responses in the anesthetized cat produced by distension of the gallbladder while recording from spinal neurol~s ~md established a stimulus-response relaticr~ between distending pressure and pressor responses. Stulrajter et al. [443] noted that intensity-related alterations in heart rate occur in dogs with distension of the gallbladder, as have o!:hers [119,2i2,420]. Gallbladder distension, in addition to dis~or,~ion of the stomach, also has been reported to reduce coronary blood flow during distension [119,184]. Changes in respiration, to the point of chronic partial contraction of the diaphragm [420], have been noted by several investigators during mechanical stimulation of biliary structures [34,126,128,167,443]. These changes in respiration were abolished by se,ctioning the right greater splanchnic nerve [126,420] although omer responses to gallbladder distension, such as vomiting and increased salivation, were not, suggesting a vagal route for primary afferents related to these responses. An interesting finding of Davis et al. [126] was that anterolateral chordotomies did not abolish pseudoaffective reflex responses to gallbladder distension in dogs unless the lesions extended into the gray matter or the dorsolateral funiculi also were cut. In these dogs, simple anterolateral chordotomies produced somatic analgesia bat failed to produce visceral analgesia. These investigators interpreted the results to mean that visceral pathways within the spinal cord were different from somatic pain pathways and likely involved numerous short ascending connections. Gallbladder distension also has been shown to produce visceromotor responses in decerebrate cats [34] and in awake, unanesthetized cats and dogs [443]. Behavioral 'escape reactions' also were noted by Stulrajter et al. [443], but a precise definition of what constituted an 'escape reaction' was not described. Neurons responsive to distension of the gallbladder have been identified in the medulla [371], white matter axons ,in the cervical spinal cord [158,160] and in T1-T5 spinal segments of the primate [20] and T2-T4 [23] and T8-T9 [86,89]; spinal segments of the cat. In work consistent with his characterization of afferents from the gallbladder, Cervero [86,87,89] demonstrated that spi-
nal neurons excited by distension of the gallbladder only were excited at distending pressures greater than 10 mm Hg (i.e., above non-pathologic:li, physiological levels). In a group of 7 neurons, accelei-ating stimulus-response functions related intraluminal gallbladder pressure to neuronal response [86,89]; pressure thresholds for activation were 25-30 mm Hg and, therefore, likely in the noxious range. In the same studies by Cervero, cardiovascular responses were noted to begin at distending pressures of 30-45 mm Hg. Somatovisceral convergence was commcn. Of 30 neurons characterized by Cervero [89], 4 were class 1, 13 were class 2 and 7 were class 3; the cutaneous receptive fields for 6 neurons were not described. Cervero also demonstrated that neuronal responses secondary to distension of the gallbladder av_d hi!i~,3, ),'e,~ were not due t,) changes in portal venuus pressure [89] Another interesting finding was that although neurons located in spinal lamina I were excited by stimulation of the greater splanclmic nerv~, none were found that were excited by distension of the gallbladder [89]. Ammons and associates [20,23] characterized 17 spinal dorsal horn neurons in the cat and 13 spinothalamic tract neurons in the primate excited by gallbladder distension. Extrapolation of stimulus-response functions relating neuronal responses to the intraluminal pressure of distension revealed population mean thresholds for excitation of 0-10 mm Hg, presumably non-noxious intensities of stiraulation. Viscerosomatic convergence was 100% in these neuronal samples and all neurons were described as class 2 or class 3. In addition to excitatory responses to gallbladder distension, Ammons and Foreman [23] also noted that the spontaneous activity of 35% of the neurons were inhibited by gallbladder distension in an intensity-depend(rot manner. They also documented viscerovisceral convergence in neurons excited by gallbladder distension; these neurons also were excited by electrical stimulation of thoracic visceral nerves [20,23] a n d / o r the intraatrial injection of the algesic peptide bradykinin [20]. The findings of Cervero [86,89] and those of Ammons [20,23] suggest different neurophysiological understandings of visceral pain. Cervero's results support a specificity theory of visceral
202
nociception where some, if not all, spinal neurons excited by gallbladder distension can be excited only by pressures that are noxious and are thus dedicated to nociception. The findings of Ammons and associates indicate that spinal neurons are excited by both noxious and non-noxious intensities of gallbladder dister.sion. Why the pressure thresholds for excitation differ between these studies is not readily apparent. Both studies examined neurons with long ascending projections and cell bodies located deep in the spinal dorsal horn. It may be significant that the neurons studied by Ammons and associates [20,23] were spontaneously active while those studied by Cervero [86,89] were not. This could be due to differences in experimental preparation and/or neuronal samples. For example, Ammons and associates examined neurons in the upper thoracic spinal cord while Cervero examined neurons in the T8T9 spinal segments. Tonic descending influences or anesthetic effects may have been more predominant in Cervero's preparation. Alternatively, there may have been increased inflammation with sensitization/facilitation of responses due to the more extensive surgical interventions in the experimental preparations of Ammons (who also electrically stimulated thoracic visceral nerves). Testis Long b~fore they undertook their scie~,tific training, male investigators realized that compression of the testicles could produce intense pain. In 1933, Woollard and Carmichael [493] undertook the experimental study of pain arising from the testicles by performing various manipulations on themselves. By using known weights (50-1000 g) to compress a testicle, they reported that pain was referred to the groin, inside of the thighs and lower back. By selectively anesthetizing nerves innervating the scrotum and its contents, they were able to demonstrate that testicular pain was localized to roughly the T10-L1 spinal levels with information traveling predominantly through the superior spermatic nerve. Subsequent investigators have concentrated on animal models of testicular pain. Kumazawa, Mizumura and associates [e.g. 253.320] and others [382] have performed extensi~,: studies examining the mechano- and chemo-
sensitivity of testicular afferents in the dog. Compression of the testicle has been described as producing cardiovascular responses and changes in respiratory rate in rats [233] and dogs [320]. Mizumura et al. [320] reported intensity-related depressor responses and suppression-facilitation of respiratory rate, minute volume and phrenic nerve activity. Depressor responses were noted with low intensity compression (30 g) whereas alterations in respiratory rate did not occur until compression by 100 or 200 g. Testicular compression also excites primate spinothalamic tract neurons [319] and rat lumbar spinal neurons [233]. In a sample of 20 spinothalamic tract neurons located at the thoracolumbar junction in the primate, Milne et al. [319] reported that 17 (85%) of these neurons were excited by compression of the ipsilateral testicle; 5 spinothalamic tract neurons in the sacral spinal cord were tested and found to have no response to testiculez" compression. Responses to graded testicular compression were similarly graded and heating of the testicle or the application of an irritant chemical (isotonic KCI) to the exposed surface of the testicle also produced excitation in these neurons. All of the spinothalamic tract neurons with testieular input had convergent somatic receptive fields located on the flank and back. Four of the neurons excited by testicular compression were excited only by noxious cutaneous stimuli (class 3); the rest were excited by both noxious and non-noxious cutaneous stimuli (class 2). Viscerovisceral convergence with input from the ,finary bladder and colon also has been noted [319] (e.g., Fig. 12). Female reproductive organs Pain origLnafing from the female reproductive organs is a conunon experience: Mittleschmerz, menstrual cramps, childbirth, pelvic inflammatory diseases or endometlfosis directly afflict roughly half of the population at least once in their life. There are numerous clinical reports related to these forms of visceral pain and the relief thereof, but comparatively little experimental research. Javert and Hardy [225] attempted to quantify the pain of childbirth by asking women in labor to compare the intensity of pain experienced during different stages of labor with a radiant heat
203
A 10 Hz]
Jk 40 mmHg
.Jt., 80 mmHg
colorectal distension
I00 gm
200 gm
voginol probe
40 mmHg
80 mmHg
colorectol distension
press
squeeze
testis compression
Fig. 12. Viseerovisceral convergence. Examples of two thoracolumbar spinal dorsal horn neurons in the rat receiving excitatory input from multiple viscera. A: peristimulus time histograms of a neuron receiving graded excitatory input from both the colon/rectum and vagina/uterine cervix. B: similar representation of another neuron with convergent graded input from the colon/rectum and testicle. Cartoons of the corresponding convergent cutaneous receptive fields are also illustrated. Both units responded to innocuous brush and noxious pinch, heat and cold applied in the receptiw-, fidd [Ness, d Gebhart, unpublished].
stimulus measured in units of dols. Pain correlated with dilation of the cervix. Prior to cervical dilation, contractions were non-painful (e.g., BraxtonHicks contractions felt prior to actual labor). However, dilation of the cervix during labor led to incrementing, graded pain with a rough equivalent of 1 dol/cm of cervical dilation. The pain of full dilation (10 cm = ] 0.5 dols) was equivalent to pain evoked by radian~ heat sufficient to burn skin; dysmenorrhea was equated with 3-4 dols. These findings have been confirmed recently using multiple verbal and non-verbal instruments to assess labor pain [71a]. What research has been performed in animals has been predominantly concerned with the way in which perineal or vaginal stimulation affects sexual behaviors (e.g., lordosis [250]) and related endocrine function or has examined the phenomenon of vaginal stimulation-produced analgesia [e.g., 247]. In animals, postural changes ~nd alterations in respiration and gastrointestinal functiov_ occur with vaginal stimulation [e.g., 115,175, Ltori, cf., 175] and numerous spinal [133,250,389] and higher-order neurons [e.g., 177,217,401,402] are excited by vaginal probing, but specific relations to nociception arising from the vagina are not readily apparent. Viscerovisceral convergence w~h
input from the urinary bladder, colon and rectum has been demonstrated [133] (Fig. 12). Pinching of the ovaries or uterine horns or stretch of ovarian ligaments has been reported to produce cardiovascular and visceromotor responses [147]. Recent work by Berkley and her colleagues [49,50,50a] in the rat has focused on primary afferents arising from the uterus and travdilig in the hypogastric and pelvic nerves Hypogastric nerve afferents were found to be sensitive to probing, distension and natural contractions of the uterus and associated ligaments and also responded in a concentration-dependent fashion to injections into the', uterine artery of the algesic chemicals bra~ykinin, serotonin or KCI and the ischemia-anoxia-related compounds CO2 and NaCN. An interesting finding of these studies was that an apparent 'sensitization' of the afferents was necessary for them to become mechanosensitive, particularly ill relation to contractions of the uterus. Alterations h-i sensitivity also were found in association with the es'trous cycle. Other viscera
Mechanical! stimuli applied to other viscera inelude pinchin~ and rubbh~g of the peric~dium and heart [Capp% of, 273;10], sp!~:zn [105,147.31 "'].
204 diaphragm [78,274,328,393], mesentery [28] or pancreas [147274], producing reports of pain and cardiovascular, respiratory and/or visceromotor responses. Most notable of these is a study in humans by Morley [328] in which the peritoneal surface of the diaphragm was irritated with a probe or surgical mop during abdominal surgery under local or regional anesthesia, leaaing to reports of pain loc-,dized ~o the top of the shoulder (homosegmental to phrenlc nerve inputs). When the skin of one shoulder was infiltrated with novocaine, the reports of pain were much reduced or abolished on the side that was infiltrated while pain in the other shoulder was unaffected. It is possible to ascribe these results to spread of the local anesthetic to the phrenic nerve or to psychological causes, but analogous carefully controlled clinical or animal experimental s.~uries to refute or confirm studies such as this have not been performed. Distension of the thoracic aorta using an inflatable rubber cylinder coupled witli a rigid core cannula so that blood flow is not interrupted has been demonstrated by Malliani and associates [293,365] to produce strong pressor responses and tachycardia in awake, unanesthetized dogs in the absence of any discernible pain reaction. Restlesshess of the dogs was noted and was equated with similar behavior that occurs in response to excessive increases in arterial pressure induced by pressor drugs. A serendipitous finding of these same investigators [291] came from experiments in which the coronary arteries of dogs were chronically cannulated. In one dog the tip of the intracoronary catheter had slipped from the lumen of the vessel into the adjacent adventitia. Injections of r~ormal saline produced a local mechanical distortion of the vascular tissue and led to immediate and reproducible 'pain reactions' with vocalization and cardiovascular~ respiratory and visceromotor changes. Weaver et al. [475] reported alterations in renal sympathetic nerve activity with distension of the thoracic aorta and with mechanical stretching of the right or left ventricles of the heart (using appropriately placed rows of sutures). Several investigators [234,298,376,445,482] have r,,ported that traction on coronary vessels, both arterial and venous, produces pseudoaffective re-
sponses in awake un~,~esthetized dogs. The pseudoaffective responses consisted of leg stiffening, salivation, limping on the left forepaw, alterations in respiration and cardiovascular changes. These responses have traditionally been attributed to myocardial ischemia, although the studies of Martin and Gordham [298] and Katz et al. [234] specifically dissociated vascular occlusion from vascular traction by employing multiple ligatures. These investigators reported that pseudoaffective responses were evoked only with vascular traction and that vascular occlusion alone did not produce pseudoaffective responses. Further, they reported that traction or tearing of the myocardium did not produce pseudoaffective responses if traction of the vasculature did not occur. Blair and associates also examined sensation ari!i:iz~g from the heart by utilizing mechanical ~'probir.g of tile epicardium and pericardium, volume loading and artificially producing premature ventricular contractions (PVCs) to excite spinal [57] and medullary [55,56] neurons. Blair and Foreman [57] reported that all spinal neurons excited by PVCs received both A& and C-fiber input from thoracic visceral nerves, while most neurons not responsive to PVCs were excited exclusively by AS-fibers. Using a blunt wooden stick to probe and forceps to pinch the epicardium and pericardium, these same investigators reported that 13 of 21 neurons excited by stimulation of thoracic visceral nerves also could be excited by mechanical stimulation of the heart and associated structures and that 13 of 23 neurons tested were excited by occlusion of the aorta or pulmonary artery with resultant increases in intraventricular pressures. Most, if not all, primary afferents from the heart [e.g., 83,295,463] and some spiny neurons [e.g., 25,60] excited by elet:trical stimulation of the stellate ganglion or inferior cardiac nerve exhibit prose-related or cardiac volume-related activity, indicating mechanosensitivity. It has been suggested [292] that cardiac p fin may actually be due to abnormal mechanical distortion or dile:ion of areas of ischemic muscle (and adjacent vasculature) and/or the sensitization/activation of these mechanoreceptors by chemical mediators (e.g., bradyldnin, discussed below). This proposal would
205
be consistent with clinical observations of cardiac pain due to mechanical stimuli associated with mitral valve prolapse, but experimentally this assertio, is neither proven nor disproven. S u m m a r y - mechanical stimuli
Mechanical stimulation of organs such as the gastrointestinal tract has been used widely both in clinical and experimental studies of visceral sensations, including pain. Isolated, mechanical pinch of most organs does not reliably produce paix~ in ht~mans, but has been useful as a visceral stimulus for mapping neural pathways in animals. Distension of hollow organs has been a more useful stimulus since pain in huraans arises pathologically secondary to this stimulus and this pain is reported ~s identical in character to pain produced experimentally. Distension of the gut has been demonstrated to be aversive to rats, and distension of both the gut and other hollow organs produces strong pseudoaffective responses in multiple species. Distension also produces vigorous, reliable and reproducible neuronal responses and both neuronal and autonomic/motor responses t¢ distension of hollow organs are inhibited by analgesic drags and other antinociceptive manipulations. Mechanical stimuli such as distension of hollow organs therefore fulfill all criteria as adequate noxious visceral stimuli. Specific responses to distension must be considered only as representative of, but not necessarily specific for, visceral nociception since distension of hollow organs also produces non-nocieeptive autonomic reflexes.
lschemia as a noxious viscera! stimuim
Interruption of the blood supply to most deep tissues, including the viscera, often, but not always, leads to pain. Of great clinical concern is the interruption of the blood supply to the heart. Other pathological conditions resulting in pain secondary to ischemia/infarction are well described (e.g., mesenteric ischemia [386], torsion of spermatic cord [431], ischenfic colitis [272] and rectal angina [136]), although myocardial ischemia is clearly associated with the greatest morbidity
and mortality. In humans, angina occurs with increased cardiac work (increased heart rate, increased blood pressure) secondary to exertion, as in the treadmill test, or seconda~ to increased cardiac work, which occurs spontaneously during rest or sleep or following a myocardial infarction [e.g. 279,404]. In the case of exertic,nal angina it is cleat that increased cardiac work leads to ischemia (noted by electrocardiograohic changes) wlfich is then followed by pain. In the case of non-excrtio~ial angina, however, it is not always clear which occurs first, ischemia (due to coronary artery disease or thromboembolic event) and the subsequent activation of reflexes leading to increased heart rate and blood pressure, which in turn leads Ito increased cardiac work, more ischemia and subsequ~ng~ain (a positive feedback loop), or increased cardiac drive (for an unknown reason), leading to ischemia and then to pain. Positive feedback loops between the activation of cardi~.c afferents and sympathetic drive to the heart have been demonstrated in numerous studies by Mailiani and associates [e.go, 293,294]. Similar alterations in sympathetic tone and cardiovascular responses have been noted experimentally in animals during occlusion of coronary vessels [71,157,204, 252,296,473], although significant differences in preparation and results exist between and within studies. For example, one study [473] reported that occlusion of the left anterior descending artery of cats led to responses ranging from ch~lges in blood pressure of - 6 0 to + 85 mm Hg and alterations in sympathetic outflow to the kidney of - 4 0 to +90~, even though the experimental preparations were stated to be identical (a-chloralose anesthetized~ carotid sinus and aortic depressor nerves cut). Subtle differences in preparation, such as the depth of aJlesthesia, and previous experimental manipulations in the same animal may have contributed to this variability. The most reproducible autonomic responses to coronary artery occlusion have been observed in spinalized animals in which all brain-stem feedback controls have been severed [e.g., 71,296]. Several investigators have attempted to minimize the influence of anesthesia by examining the effects of coronary artery occlasion in awake uvanesthetized, lightly anesthetized (determined by
206 presence/absence of certain motor reflexes) or decerebrate preparations [70,234,298,323,445,481, 482]. These studies reported that occlusion of coronary vessels (arterial or venous) produced pseudoaffective responses consisting of cardiovascular changes, alterations in respiration, increased restlessness, increased salivation a n d / o r leg stiffening/limping. These responses began coincident ~t.h traction on the vessels and terminated as soon as the traction was released. A provocative finding of Sutton and Lueth [445] was that the accidental transection of a coronary vessel being occluded resulted in cessation of the pseudoaffective responses. That is, in spite of a complete cessation of blood flow, pseudoaffective responses were terminated, suggesting that cardiac pain is either due to mechanical traction upon vasculature or that nerves which carry cardiac nociceptive information from a specific region of the heart travel exclusively with the main coronary vessel supplying that region with no overlap from other nerves/vessels. As indicated earlier when reviewing mechanical stimuli, subsequent researchers using the preparation of Sutton and Lueth [234,298] dissociated the stimulus of vascular traction from occlusion of the vessel and reported that occlusion of coronary vessels without traction did not lead to pseudoaffective responses, but that traction without occlusion (using multiple ligatures pulling in 3 directions) did produce pseudoaffective responses. Thus, interruption of the blood supply to the myocardium may not be an adequate noxious stimulus, but traction on the blood vcs~el~ aione o~~coupled with ischernia is an adequate stimulus. To the best of our knowledge, the findings of these last two rarely cited papers have not been reinvestigated. Myocardial ischemia has been demonstrated in numerous studies to activate both myelinated and unmyelinated cardiac sensory fibers beginning 15-30 sec following occlusion of coronary vessels [e.g., 70,83,280,460,4661. Various investigators have attempted to relate this increase in activity with increases in local concentrations of endogenous compounds such as potassium, serotonin, bradykinin or prostaglandins, all of which also increase ~;ith cardiac ischemia [e.g., 62,204,238,478]. The relationship between these compounds and cardiac
ischemia only has been shown to be correlative since neuronal responses to bradykinin may be dissociable from responses to ischemia. Vogt et al. [466] were able to demonstrate that acetylsalicylic acid reduced the responses of cardiac afferents to the intraarterial administration of bradykinin but produced no reduction in responses of the same afferents to coronary artery occlusion. This study was not quantitative. However, similar studies by Longhurst and Dittman [282] in which abdominal afferents (gallbladder, pancreas, mesentery, liver, gut) excited by ischemia were examined, found that 10-20% of ischemia-sensitive fibers were not excited by intraarterial administration of bradykinin. There was a relation between the two stimuli as some of the abdominal afferents characterized by these investigators were sensitive to ischemia only after being 'sensitized' by bradykinin or prostaglandins; prior to exposure to these compounds, these abdominal afferents were not excited by ischemia. Neurons excited a n d / o r inhibited by coronary artery occlusion have been characterized in the spinal cord [58,171,456] and the medulla [53,54]. All of these studies examined the effects of coronary artery occlusion on the spontaneous activity of neurons that responded to the electrical stimulation of thoracic visceral nerves. Responses to occlusion were more commonly excitatory, but could be inhibitory, and were generally small in magnitude. Of 105 spinal neurons characterized by Foreman and Ohata [171]; less than half responded to coronary artery occlusion: 33 were excited, 3 were inhibited, 40 were unaffected and 29 unresponsive neurons were excluded from the study post hoc. Of the 33 neurons excited by coronary artery occlusion, 16 were excited at a latency of less than I sec, a time prior to the onset of any electrocardiographic changes, and hence these neurons were presumably mechanosensitive. The other 17 neurons began responding 2 sec or more following vascular occlusion, typically prior to the onset of electrocardiographic changes. The peak rate of activity during occlusion was compared with the mean rate of spontaneous activity (no values given) and an average increase in activity of approximately 9 Hz was reported. Blair et al. [58] reported that 17-20 of 33 spinal projection
207
neurons tested were excited by coronary artery occlusion and increased their activity from a mean spontaneous rate of 12 Hz to a mean peak rate during occlusion of 20 Hz. Other findings by Blair et al. [58] were similar to those of Foreman and Ohata [171]; spinal neurons excited during occlusion of coronary vessels had convergent cutaneous receptive fields centered in the dermatomes corresponding to the spinal segments of recording and hence located on the chest and upper limbs. Some of these spinal neurons were class 2 or 3, but exact numbers were not specified for neurons excited by occlusion. Obviously, experimental studies of myocardial ischenda are of potential clinical significance. Studies of spinal neurons receiving afferent input from the heart, however, suggest that even transient experimental manipulations may have profound effects on the responses measured and also alter other parameters (e.g., blood pressure, heart rate) that are not easily controllable. Hence, the difficulty in interpreting results from such experiments is apparent. For example, the character of the neuronal response to coronary artery occlusion may change with repeated experimental ischemic episodes [192a] (see Fig. 13). Clinical evidence suggests that cardiac pain is similar, if not identical, to other visceral pains in intensP.y and quality. However, given the fact that the heart is vital to the survivability of the organism, it is possible that special systems may have evolved to control cardiac pain and so are responsible for the phenomenon of 'silent' ischemia - - a clinical entity where ischemia of the myocardium is apparent electrocardiographically with no sensation of pain. Silent ischemia may not be unique to the heart, however, as infarcted bowel often does not become symptomatic until the onset of peritonitis. Studies in which ischemia/vascular occlusion have been used as visceral stimuli in other organs are few. Notable is a recent study by Ammons and Sinha [27a] in which 5570 of 67 neurons in the cat T11-T12 spinal cord excited by electrical stimulation of the renal nerve also were excited by occlusion of the renal artery. Similar to neuronal responses to coronary artery occlusion, these neurons exhibited responses coincident with the onset
|
]15 Hz
i st
3rd
5fh
I
i
7fh
t coronary.... t occlusions
Fig. 13. Visceroceptive neurons - ischemic sdmuh. The responses of a thoracic dorsal horn neuron in the cat to repeated coronary artery occlusions (left anterior descending artery) are illustrated as peristimulus time histo~ams representing responses to the 1st, 3rd, 5th and 7th occlusion; occlusionswere 60 sec in duration and administered every 10 rain. At bottom is a cartoon illustrating the convergent cutaneous receptive field of this neuron whichwas excited by noxious pinch [192a].
208
of occlusion (suggesting mechanoreceptive input) followed by a second response 30-60 sec later (presumably due to ischemia). Studies utilizing the distensior~ of hollow organs as a noxious stimulus also may be partially examining the effects of ischemia. For example, Ohman [360] reported that the blood flow within the small intestine of rats drops to near zero when the intraluminal pressure exceeds 60 mm Hg. Some studies have differentiated responses to ischemia from responses to distension [e.g., 452], but it is likely that ischemia has an effect on responses to repeated distensions. Pseudoaffective responses such as altered respiration and cardiovascular changes have been examined secondary to the occlusion of various abdorninal blood vessels [e.g., 47,414], but usually in the context of cardiovascular regulation by presumed abdominal baroreceptors or respiratory regulation by intestinal chemoceptors. Animal models of chronic mesenteric ischemia have been developed [e.g. 386], but at present these investigations have so~ght to examine the pathophysiology of this disease and have not specifically examined ischemia as a noxious stimulus. Modulation of responses tc coronary artery occlusion has been noted in one study by Pearcy et al. [376] in which the administration of morphine subjectively reduced pseudoaffective responses of dogs to coronary artery traction/occlusion.
Summary- ischemia Ischemia is a well-accepted etiology of pain from visceral tissues, particularly in the case of diseased oi ~ recently traumatized (post surgery) tissue, and may produce pseudoaffective responses in animals, hence fulfilling basic criteria as an adequate noxious viscera! stimulus. Ischemia is not, however, a reliable stimulus since ischemic myocardium or infarcted bowel is often 'silent' clinically and recognized solely by alterations in the electrocardiogram or the onset of associated symptoms such as peritonitis. Similarly, reflex and neuronal responses to ischemia also have exhibited marked variabi~ty within and between preparations. Some of the variability may be due to compensatory systems activated by the stimulus ~tself (e.g., opening of collateral vascular pathways), but because of the unreliability of re-
sponses to this stimulus, vascular occlusion is not ideal as a noxious visceral stimulus. Likewise, modulation or comparison of reflex or neuronal responses to ischemia-producing stimuli may be questionably meaningful in the presence of marked variability. It is possible that ischemia acts only as a modulator of mechanoreceptive visceral inputs and the variability observed in responses to ischemia may be due to the presence of preexisting pathology or mechanical distortion of the viscera secondary to a localized change in compliance/ muscle tone due to focal ischemia. Despite this difficulty in the control of and variability in responses to ischemia-producing stimuli, the clinical importance of ischemia in organs such as the heart necessitates continued, vigorous re,search with an emphasis on appropriate experimental controls.
Chemical stimuli as noxious visceral stimuli
General Algogenic substances have been used extensively to produce, by definition, pain in skin, muscle, ligaments and viscera. These substances have been applied topically to exposed surfaces and injected into the blood supply of various organs. The topical administratiou of algogenic substances limits the site of action to a well-localized isolated surface of the organ examined (e.g., epicardial surface). The intraarterial or intravenous (e.g., intr~porta!) injection o!' these substances produces activation of neural afferents in all layers of a given organ or group of organs, depending on the site of injection, but also may have systemic effects. Early studies, such as those by Moore and associates [322,323], investigated the sensibility of arteries and the visceral structures they supplied by injecting hypertonic saline, acidic or basic solutions of isotonic saline, lactic acid and various chloride, sodium or potassium salt solutions and observing pseudoaffective responses (respiratory changes, visceromotor responses and vocalization). Using this approach, they described pathways of visceral afferents to the spinal cord by performing selective lesions of nerves. For example, Moore and Singleton [323] injected isotonic KC1 and
209
lactic acid into the left coronary artery of cats and produced profound pseudoaffective responses. When the left sympathetic chain from the stellate ganglion to the .'1"7spinal level was removed, pseudoaffective responses did not occur until marked ventricular dilation (secondary to the lactic acid) and advanced asphyxia had developed. Lactic acid was used because it was felt to be 'physiological' (i.e., produced by Jschemic tissue). However, nonphysiological concentrations of up to 20% lactic acid were requi=ed to produce reliable pseudoaffective responses. Numerous other 'natural' compounds such as serotonin and potassium chloride also are algogenic, but again at questionably 'physiological' concentrations. However, bradykinin is a natural substance generated in response to tissue damage which is algogenic in concentrations assumed physiological. Bradykinin produces pain in humans when injected intracutaneously [e.g., 31,32, 113,218] or intraarterially [72,108,173,427]. In animals, using methods similar to those of Moore and associates, vocalization and pseudoaffective visceromotor responses, cardiovascular changes and respiratory changes are produced when bradykinin is administered intraarterially or intraperitoneally [137,194,195,275] in microgram dosages. Although the case for bradykirtin as an endogenous algogenic gubstance is strong, the precise role of bradykinin and its contribution to visceral nociception are not, as yet, completely defined. Bradykinin may not be the primary stimulus in visceral pain produced either mechanically or secondary to isehemia, but it clearly has modulatory effects on the same primary afferents and spinal neurons that are affected by these stimuli. Hence, bradykinin and other algogenic substances have been utilized extensively as noxious visceral stimuli.
Abdominal/pelvic organs Algogenic chemicals injected intraperitoneaUy have been the most widely used presumptive noxious visceral stimuli. The writhing test, a visceromotor response to the intraperitoneal administration of algesic chemicals, is commonly used in the screening of drugs, particularly novel or 'weak,' analgesic or ant[inflammatory drugs [e.g.,
2 ~•.,,,-,,,,-,-~, A1 '7 AA'71~.
It consists of characteristic visceromotor 'stretching' or 'writhing,' an alternating abdominal flexion-extension. Algogenic chemicals which have been employed include acetic acid, phenylquinone, hypertonic saline, bradykinin, serotonin, KCI, ATP, acetylcholkne and MgSO4 [e.g., 196,208,447], some of wtfich have been demonstrated to produce an acute peritoneal inflaz~artation [e.g., 357], presumably via a prostanoid mechanism [135]. Justification fgr the intraperitoneal administration of bradykinin as a noxious visceral stimulus was provided by Lim et al. [276] who examined the effects of intraperitone.,d injections of bradykinin in humaas. These investigators plzced a 20-30 cm long catheter petcutaneously into the peritoneal cavity and administered doses of 4-16 pg of bradykinin every 15 min for more than 2 h. Twenty-two percent of those people tested reported little or no pain, even after manipulation of the intraperitoneal catheter and repeated injections of 16 #g of bradykinin. These people were classified as hyporesponders and excluded from the study. Of those patients who did respond, objective measures of pain included grimacing and/or vocalization on the first injection of bradykinin; repeated injections led to reduced responses (tachyphylaxis). Subjective reports of pain were genelally of cramping or colicky pain, pressure/distension/ 'gas' pain or burning pain, alone or in combination. Aspirin, amphetamine and meperidine all gave pain relief to these individuals. Interestingly, aspirin given intraperitoneally was much more effective than when given orally, suggesting that responses to bradykinin are dependent on local inflammatory/prostanoid-related processes and not due to a direct action on chemosensitive nerve fibers. Pioneering research by Khayutin and associates [237] related chemosensitivity of the cat intestine (intraarterial injection of algogenic substances) to previously published pain thresholds in humans (cutaneous or conjunctival application of the same substances). Using a preparation in wlfich a loop of cat intestine was isolated and perfused (~ith nerves intact), these investigators were able to produce neurogenically mediated dose-dependent increases in systemic arterial blood pressure by
210
adding known concentrations of algogenic substances (e.g., KCI, capsaicin, bradykinin) to the intravascular intestinal perfusate. Brisk pressor responses were associated with concentrations of the algogenic substances previously demonstrated to produce pain in humans when injected into blister bases, intradermally or when applied to the conjunctiva. The use of chemic'efl!y similar, but nonalgogenic, substances such as t ryptophan led to weak dose-dependent pressor responses which these investigators attributed to noa-nociceptive reflexes. Frank [174] reproduced these findings and made a more extensive case for the neurogenic nature of the response. Other investigators have utilized similar techniques to restrict the application of algogenic chemicals to afferents from the small intestine [440,441], liver [35], spleen [75,194,195,275,311,458], stomach [281] and other abdominal organs [16a,224a,270] and examined their effects on cardiovascular parameters [16a, 35,74,224a,270,281,311,440,441,458], sympathetic nerve activity [74,311,440,441,458] or spinal unit responses [16a]. Cardiovascular responses were typically pressor, although mixed responses and even depressor responses [e.g., 35] were reliably produc,:d. A comparison of the cardiovascular responses on an organ-by-organ basis is confounded by differences in preparation and species. Several electrophysiological studies in which bradykinin or acetic acid was given intraperitoneally [e.g., 76,465] reported only inhibitory inputs to lumbar spinal and trigenfinal dorsal horn neurons. A study by Guilbaud et al. [192] selectively activated intestinal/colonic afferents by injecting bradykinin or acetylcholine interarterially into a collateral of the inferior mesenteric artery. Twenty of 20 spinal interneurons in the lower thoracic/ upper lumbar spinal segments excited only by non-noxious cutaneous stimuli were unaffected by the injections. Of 27 neurons excited by both noxious and non-noxious cutaneous stimuli (located predominantly in lamina V), 8 were excited by the injections, 14 were inhibited and 3 had mixed inhibito~j-cxcitatory responses. Other studies have demonstrated excitatory responses of spinal neurons to bradykinin excited by other v/sceral stimuli, such as colonic [e.g., 307,308,340, 343,345] or urinary bladder [307,308] distension.
,20sl15Hz
t
ep| Bk
t
AA Fig. 14. Visceroceptive neurons - chemical stimufi. Above, peristimulus time histogram illustrating the response of a thoracic dor~! horn neuron in a cat to the epicardial application (soaked pledget) of 10/Lg bradykinin (epi Bk). Below, a similar representation o£ the response of a sacral dorsal horn neuron in a rat to the appfication of a 5~ acetic acid solution (AA) to the colorectal mucosa. The corresponding convergent cutaneous receptive fields where pinch also gave excitatory responses are illustrated at the right [192a and Ness and Gebhart, unpublished].
Illustrations of typical neuronal responses to bradykinin are given in Fig. 14. A potentially confounding factor associated with the use of bradykinin to excite abdominal and pelvic afferents is that bradykinin may lead to a reflex contraction of smooth muscle. Floyd et al. [162,163] demonstrated that mechanoreceptors in the urinary bladder that were apparently excited by bradykinin were not chemoreceptive, but instead were excited secondarily to the reflex contraction of the bladder via a spinal reflex loop. Since distension or contractions of visceral smooth muscle produced by non-algogenic substances such as bethanecol [285,363] also lead to cardiovascular responses, the interpretation of responses to bradykinin must be carefully judged. Some investigators have reported that cardiovascular responses to bradykinin are greater than responses to bethanecol, even at dosages of bethanecol which produce markedly greater contractions of smooth
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muscle [e.g., 285]. An interesting tinding is that capsaicin, which affects substance P-containing nerve fibers, leads to strong cardiovascular responses but causes no co,-,.traetion of smooth muscle, suggesting that bradykinin and capsaicin may act on different populations of afferents. The topical admirdstrations of algogenic substances on the serosal .~urfaces of abdominal organs exposed by laparotomy are experimental analogues to the diffuse intraperitoneal injections ex~'.~'~! l~y L~,-~ ~-:. al. [276], but allow for more precise localization of the stimulus. Longhurst, Ordway, Weaver and associates all have demonstrated that the topical application of capsaicin a n d / o r bradykinin to the gallbladder [297,362, 413,438,468,469], stomach [285,297], pancreas [364] or small intestine [311,363,413,438,440,441,474] leads to sigrfificant respiratory changes [413,469], cardiovascular changes [285,297,311,362-364,438, 440,441,46~A74] and alterations in sympathetic nerve activity [311,440,44~,,,,-,1. " "" ~~ As v:ith the intravascular injection of algogenic substances, the reported cardiovascular responses have been varied, some investigators reporting consistent pressor responses, others depressor responses. Again, these differences appear to be species- or preparation-dependent and an organ-by-organ comparison between laboratories/preparations is of little value. The clear conclusion drawn from such studies is that chemical stimulation of the viscera produces pseudoaffective/autonomic responses. Numerous clinical observations in patients with esophagitis, gastric/peptic ulcers or gastritis indicate that chemical irritants such as stomach acid produce pain when in contact with inflamed mucosa. Unfortunately, most experimental studies restricted their use of algogenic substances to topical application to the external surface. Some studies did apply chemicals mucosally or intraparenchymally. For example, Smits and Brody [432] injected bradykinin into the substance of the kidney and reported cardiovascular responses. Giuliani et al. [186] reported similar responses with an application of capsaicin to the urinary bladder and Abelli et al. [3] evoked vigorous visceromotor responses with the instillation of xylene (10-100%) ii~to "-m~-urinary '-u~,~uu~r' - "~-' - - of rats.
Likewise, Ordway and Longhurst [362] were able to produce dose-dependent cardiovascular responses by applying bradykinin or capsaicin to either mucosal or serosal surfaces of the gall bladder. However, Longhurst et al. [285] were unable to produce cardiovascular responses by application of capsaicin or bradykinin to the stomach mucosa. 1'he application of algogenic substances to mucosal surfaces has been utilized clinically for years in the form of the widely employed Bernstein test [51]. In this test, 0.I N l:ydrochloric acid is infused onto the mucosa of the lower esophagus. Reports of chest pain and upper limb pain similar, if not identical, to cardiac angina resui~ when some form of pathology is present; normal, heaLLbv people typically do not experience pain in this test. Other human studies have applied algesic chemdcals to the mucosal surface of the stomach and observed mixed results [80,203]. Wolf and associates [cf., 203] reported that the application of acid, NaOH, mustard oil and other algogenic substances produced no responses from a patient when the mucosa of his stomach (reached via a gastrostomy) was pink and healthy. Distension pressure thresholds to produce pain from the stomach were near 35 mm Hg at these times. If, however, the mucosa was inflamed or engorged spontaneously or due to the application of mustard powder, these same substances produced marked pain (and resentment) and the distension pressure threshold for production of pain dropped to 20 mm Hg. Theobald [455] described a similar phenomenon; the application of a silver nitrate cautery or tongs to the uterine cervix produced no pain or sensation in 'healthy' females whereas the same manipulation in women sufferring from dysmenorrhea (i.e, had sensitized uterine tissue) produced abdomina! pain which radiated to the thighs, loins, groin and sacral back and was of sufficient intensity to xequire morphine. McLellan and Goodell [cf., 203] have described a similar phenomenon in the urinary bladder of humans and Grace, Wolf and Woolf [(~f 203] in the colon reached via a colostomy. Because human reports of pain due to the administration of algogenic substances to mucosa are dependent on preexisting pathology, this may explain why so few posi-
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tive experimental animal studies have been described. Recently, irritant chemicals have been infused into the lumen of hollow organs such as the esophagus [181], urinary bladder [197,246,305,306], colon (e.g., Fig. 1i) and pancreas [e.g., 259,400] to establish an inflarmnatory condition which eventually leads to visceral hyperalgesia or sensitization of a specifically chemosensitive subset of visceral primary afferents. McMahon and Abel [306] demonstrated that the urinary bladders of chronic decerebrate rats became hyperexcitable following treatment intracystally with turpentine, mustard oil or croton oil. Additionally, the rats also appeared to be hypersensitive to noxious stimuli applied to the tail or caudal abdomen (same spinal segments as urinary afferent input), but had inconsequential changes in responses to noxious stimuli applied to the hind limb or rostral abdomen, suggesting concomitant somatic hyperalgesia as is observed clinically in humans secondary to visceral pain. Simi!.arly, Garrison et al. [181] observed that acute inflammation of the esophagus produced by turpentine leads to a decreased volume threshold for activation and increased response of spinal neurons excited by esophageal distension. Clinically, inflamed viscera are the most common sources of abdominal visceral pain and so extensions of these studies will be of great basic scientific and clinical interest. Thoracic organs
Algesic chemicals, in particular bradykinin, have been widely employed in studies of cardiac nociception. Justification for the use of bradykinin to examine cardiac nociception is based on the correlative findings of Kimura et al. [238] and Hashimoto et al. [204] that the concentration of bradykinin increases in coronary sinus blood after the experimental occlusion of a coronary artery. As a consequence of these studies, numerous laboratories have employed bradykinin as a noxious stimulus to evoke cardiovascular responses [e.g., 156,190,294,356,366,394,435,436], ,?terations in sympathetic nerve activity [156,394] and responses in primary afferents [e.g., 38]. Pagani et al. [366] reported that in awake unanesthetized
dogs,which had been allowed to recover 3 weeks from intrathoracic surgery, the intracoronary administration of bradykinin (10-300 ng/kg) produced graded piessor responses but no 'pain ~actions' (e.g., vocalization, visccromotor responses), even at doses up to 2000 ng/kg. Bradykinin administered to acutely prepared, anesthetized dogs, cats or primates produced variable effects, suggesting sensitivity of the preparation to anesthetics or species differences. Malliani [291] suggests that a component of the variability of responses to visceral stimuli may be due to inputs from somatic structures, disrupted during the experimental surgical preparation. Neurons responding to the epicardial or intracardiac administration of bradykinin (e.g., Fig. 14) have been characterized by Blair, Foreman and associates in the medulla [53,56] and upper thoracic spinal cord [18,22,25,27,57,58,60,61,171, 456,476]. Like neuronal responses to coronary artery occlusion, responses to either the epicardial or intraatrial administration of bradykinin were observed to be relatively small in magnitude. For example, Blair et al. [60] reported that the activity of 30 of 41 primate thoracic spinothalamic tract neurons increased their mean discharge rate from 11 Hz to a mean peak response of 29 Hz. In a subsequent study in the cat, 36% of 64 spinal units were excited by intracardiac bradykinin, increasing in activity from a mean 4 Hz to a peak of 20 Hz [61]. Similar also to neuronal responses to occlusion of coronary arteries (e.g., Fig. 13), responses to bradykinin may change with repeated exposure. Blair and associates [60,61,476] observed that repeated administration of bradykinin led to markedly reduced responses (i.e., tachyp.hylaxis) in 517o of the total 67 neurons tested. Tachyphylaxis also has been noted previously in studies of cardiac primary afferents [e.g., 38] and confounds attempts to compare responses to bradykinin quantitatively. Whether tachyphylaxis to bradyldnin develops may be related to species a n d / o r the spinal unit studied. For example, Foreman [60 and personal communication] reports that reliable and reproducible responses to bradykinin are observed in - 6 0 % of primate spinothalamic tract neurons, but that responses of spinal neurons in the cat to the same stimulus are less reliable and
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not as reproducible. The interval between repeated testing and the dosage also likely coiitfibutes to the results. Dosages and routes of adm.,:nistration of bradykinin differ between studies and often within studies. Intervals between testing are often not controlled, but tachyphylaxis to bradyldnin is evident at intervals of 10 min and less [60,61,192a]. Similarly, Blair [53] observed that reticulospinal neurons generally did not respond to every application of bradykinin. Viscerosomatic convergence is presumed to be common in neurons excited by epicardial or intraatrial administration of bradykinin; the characteristics of these neurons have not been specifically described but instead grouped with the characteristics of numerous additional neurons responding to the electrical stimulation of thoracic visceral nerves. Similarly, the terminations of long ascending projections of neurons responsive to bradykinin have not been fully addressed, but spinoreticular and spinothalamic neurons form at least a subset of these neurons. Another interesting finding is that bradyldnin may produce a sensitization of some spinal neurons to cardiac mechanical stimuli, these neurons beginning to demonstrate pulse-phasic activity following the administration of bradykinin [25,60]. A troublesome finding of several experimental studies is that cardiovascular reflexes produced by epicardial or intraatrial administration of bradykinin began prior to the onset of a neuronal response. For example, the latency to the change in blood pressure produced by bradyldnin was significantly less than the latency to the onset of spinal unit responses [61]. Since the sample in this study was exclusively spinoreticular and spinothalamic tract neurons, these results suggest that these neurom are not related to the production of pseudoaffective responses and could potentially be excited secondary to the pseudoaffective responscs. Capsaicin also has been applied epicardially and into the coronary blood supply by Staszewska-Wooley et al. [437] with directly opposite effects. That is, epicardial application of capsMcin increased blood pressure and heart rate, whereas the intracoronary injection of capsaicin decreased blood pressure with a transient bradycardia. Fol-
lowing bilateral vagotomy, intracoroaary injection of capsaicin increased blood pressurc and heart rote, suggesting antagonistic effects of the activation of vagai and ~,y.mp~,,,,.,,,.t"~':" ..... ,,,.,.,~rr . . . . ~.,,,o'~ ,,r. . ~. ., m t h e heart. The other major organs of the thoracic cavity are the lungs. Studies of reflexes originating from the lungs are numerous, but studies of sensation are few. Recent reviews by Painta! [369] and Widdicombe [485] have poi:aed out that major gaps in knowledge exist in lung sensation. It is debatable whether pain ever originates directly from the lungs. Pain is often experienced in patients with lung cancer, but only after involvement of the pleura. Sensations or tightness, rawness, irritation or breathlessness can be attributed to the activation of afferents from the lungs and airways, but because studies of lung sensation have utilized the intravenous administration of chemi.~a!s such as lobuline or phenyldiguanide [e.g., 221], reports of gubsternal burning and discomfort are questionably of lung origin. Like the heart, because of their vital role in the survivability of the organism, the lungs may be affected differently by nociceptive stimuli and, because of their direct exposure to the external environment, have developed special protective reflexes to guard against noxious inhalants. The administration of substances such as capsaicin and phenyldiguanide into the lungs has been reported to produce cardiovascular and respiratory reflexes such as cough, sniffing and laryngospasm [e.g., 84,489], but other pseudoaffecrive responses such as vocalization or visceromotor reflexes have not been reported. Modulation Most studies of modulation of visceral pain produced by chemical stimuli have utilized the writlfing test described above. Although it has been used to examine endogenous analgesia systems [183], the writhing test has been used almost exclusively to evaluate the antinociceptivc or antiinflammatory efficacy of drugs. The efficacy of antiinflammatory drugs, specifically the salicyiates, in the writhing test is actually an argument against the test being representative of visceral pain since salicylates have very limited efficacy as analgesics for visceral pain in humans [161], with
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the exception of dysmenorrhea. This lack of efficacy is somewhat surprising since the salicylates and other antiinflammatory drugs are efficacious against deep pains arising in muscle, bone and joints and clinically it would appear that the etiology of much visceral pain is a sensitization of visceral structures by inflammatory processes. A major difference between the clinical and experim c n ~ situations is that experimentally, antimo flammatory drugs are given as pretreatments and so may effectively prevent inflammation before a presumed sensitization process starts. Clinically, antiinflammatory drugs are given after an inflammation has developed and so may only reduce (rather than prevent) inflammation and not affect the presumed sensitization process. Studies of abdominal [438] and cardiac [e.g., 436,461,466] afferents h~ve demonstrated that bradykinin-induced responses are significantly reduced by the administration of antiinflammatory drugs, an effect that can be reversed by the administration of PGEj, PGE 2 or PGI 2, but not by PGF2~ [438]. A facilitation of responses to the epicardial administration of bradykinin has been observed with the coadministration of PGE~ or PGE 2 [339,436]. It is possible that the contrasting effects of the intracoronary administration of bradykinin reported by Pagalfi et al. [366] in which vocalization and agitation were evoked in the immediate postsurgical recovery period (products of inflammation present), but were absent after additional healing, represent a sens',tizing, facilitatory or per~r.issive effect of prostaglandins on bradyldnin-sensitive visceral afferents. ~pinal neurons excited by the intracardiac administration of bradykinin have been demongtrated to be subject to inhibition produced by electrical stimulation of the vagus nerve [18,19, 456], nucleus raphe magnus [22], periventricular gray in the diencephalon [27], PAG in the midbrain [99], dorsolateral pons [68] and distension of the urinary bladder [69]. Stein et al. [440] reported that the pretreatment of adult rats with capsaicin led to a reduction in the cardiovascular aad sympathetic nerve responses to the topical administration of bradykinin to the small intestine and Abelli et al. [3] have reported that morphine (2-5 mg/kg s.c.) and baclofen (2.5-10 m g / k g s.c.) produced
dose-dependent inhibition of the visceromotor response to intracystal xylene. Summary - chemical stimuli
The administration of algogenic substances to viscera leads to autonomic, visceromotor and neuronal responses suggestive of nociception and, when administered intraperitoneally in humans, produces reports of pain in approximately 8070 of individuals tested. Hence, chemical stimuli injected intraperitoneaUy fulfill criteria as adequate noxious visceral stinmli. Presumably, they also are noxious when administered elsewhere and by different routes. Foremost of the algogenic substances is bradykinin, which is a natural compound formed during tissue damage. Frank tissue damage (e.g., cutting, burning) does not reliably produce reports of visceral pain, but does result in the production of bradykinin. This observation, coupled with reports that the intracoronary injection of bradykinin in the absence of associated pathology (e.g., post-surgical trauma) does not produce behavioral responses suggestive of pain, suggests that bradykinin is not sufficient as an adequate, noxious visceral stimulus. Reports of sensitizing effects of bradykinin on mechanosensitire primary afferents and dorsal horn neurons suggest that bradykinin may act as a modulator or co.stimulant of visceral sensory systems rather than as a primary stimulus. Neuronal respomes to bradyldnin arc not reliably reproducible. Hence :h~ util~ty of ~his stimulus ~or quantitative studies investigating the substrates or modulation of visceral nociception is limited to cases where the dosage and interval between dosages is controlled and responses are established as reproducible.
Final summary and comments Models o f visceral pain
Clinically, visceral pain can be sun~'narized as follows. Disease originating in the viscera leads to pain which initially is dull, achy and poorly localized. Eventually, pain becomes more localized and is "referred' to those somatic structures with afferents entering the same spinal segments as the afferents from the viscera; hyperalgesia in those
215 same somatic structures may be associated with the visceral pain. Additionally, disease processes originating in the viscera may spread to involve the parietes (somatic pleura and peritoneum) and so may be associated with referred/localized pain and hyperalgesia of somatic origin. Associated with both visceral and parietal pain are strong motor reflexes which may lead to muscle spasm and additional localized/referred pain and hyper~ algesia of somatic origin. Needless to say, the clinical picture of pathological 'visceral' pain is not simple and often involves pain of both somatic and visceral origins. Regardless, both human and non-human experimental investigations of visceral pain have been performed in the context of theories utilizing 'simple' mechanisms to explain all observations. Theorists of visceral pain diverge into 2 main groups historically, the pefipherafists and the centralists. Sturge in 1883 [444] first promoted the centralist hypothesis that activation of visceral afferents set up a 'commotion' in the gray matter of the spinal cord, leading to strong autonomic and motor reflexes. Sturge's ideas were further refined by investigators such as Ross [403], Head [207] and others to be finally stated in 2 main forms: by MacKenzie [287] as the 'irritable focus' or convergence-facilitation theory, in which the activation of visceral afferents leads to changes in the excitability of multiple spinal units, including those responsible for segmental motor outflow and somatic nociceptive sensc,ry pathways, but not to the direct activation of spinal neurons; and by Ruch [408] as the convergence-projection theory, in which the excitation of visceral afferents leads to the direct activation of neurons receiving both visceral and somatic inputs with cell bodies in the spinal cord and long ascending projections to the brain, specifically to the thalamus. In Ruch's convergence-projection theory, the brain misinterprets activity in the viscerosomatic neurons as indicating excitation of somatic afferents since visceral inputs are normally silent. Other variations on centralist themes propose that viscerosomatic convergence occurs exclusively at thalamic or cortical levels. Periphera!ist theories of visceral pain propose that vasoactive or 'sensitizing' factors are released
into cutaneous ~nd deep somatic tissues, leading to hyperalgesia and/or tonic 'referred' pain from those structures [e.g., 127]. Peripheralist theories also fell into 2 main ~oups: those stating that axon reflexes in sensory neurons with dichotomizing fibers projecting to both somatic and visceral structures were responsible for the release of these factors, and those stating that increased sympathetic motor activity was responsible for the release of these factors. Proposed wiring diagrams are varied and include sensory neurons with dichotomizi,g fibers branching to cutaneous, deep somatic and visceral tissues [479], sensory neurons with dichotomizing fibers having branches to visceral and somatic deep tissue paired with others branching to somatic deep tissues and skin (i.e., visceral stimuli produce deep tissue hyperalgesia which produces cutaneous hyperalgesia [430]), sensory neurons with direct excitatory connections with postganglionic, prespinal, ~ympathetic motor neurons [377], and neurons producing excitation of spinal preganglionic sympathetic motor neurons vi~ direct or polysynaptic connections. Support for both peripheralist and centralist theories derives from numerous clinical experiments using virtually identical approaches and obtaining relatively similar outcomes, but having radically different interpretations. Using local anesthetics or nerve sections to abolish/attenuate cutaneous (and likely deep tissue) sensation in humans, investigators reported that both pathological and experimental visceral pain was typically attenuated [66,110,141,229,328,455,477,494]. The peripheralists pointed out that the visceral pain was 'markedly' attenuated in these studies and that somatic pain typically outlasted the presentation of experimental visceral stimuli [e.g., 78]. The centralists pointed out that viscerosomatic pain was immediate in onset with experimental stimuli and could not be comp!etely abolished by peripheral manipulations. In most of these early studies it was unclear whether the visceral pain studied was pain referred to somatic structures or pain originating in hyperalgesic somatic structures. An example is provided in a case report by Cohen [110] iv which a patient with angina localized pain to an amputated 'phantom' limb prior to the onset of pain in his chest. Following a
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regional block of the brachial plexus, this patient then experienced anginal pain initially in the chest and later in the 'phantom' limb. Cohen also reported that blistering of the skin or injection of hypertonic saline intradermally led to a somatic hyperalgesia and that visceral pain previously localized to other homosegmental sites became referred to the sites of hyperalgesia. These findings, and those of others using local anesthesia or nerve transection, suggested that visceral pain has two components, one central and the other peripheral, or, alternatively, that central nervous system alterations in excitability occur which are affected by a summation of tonic visceral and somatic inputs. At present there exists neuroanatomical, dectrophysiological, behavioral and physiological evidence that supports components of all theories related to the localization of visceral pain. There is evidence for the existence of dichotomizing fibers in the periphery, although they are clearly insufficient in number to account for viscerosomatic convergence. There is also considerable support for Ruch's convergence-projection hypothesis since numerous spinal dorsal horn neurons having both visceral and somatic inputs and long ascending projections to the brain have been identified. There is support for M~cKenzie's convergence-facilita. tion hypothesis since clinically and experimentally, some responses to visceral stimuli increase with repeated or sustained exposure. There is also support for theories related to increased sympathetic motor activity; visceral stimuli excite sympathetic preganglionic motor neurons in the spinal cord and directly activate sympathetic postganglionic neurons through direct connections in autonomic ganglia. Further, increases in sympathetic outflow have been related to pathological hyperalgesia phenomena such as reverse sympathetic dystrophy syndrome.
A proposed model of visceral pain In an attempt to reconcile these various theories of visceral pain with clinical observations and the experimental results reviewed here, the following model of visceral pain is proposed. It is acknowledged that the model is incomplete and does not adequately describe all of the compo-
nents of visceral pain. However, it is consistent with observations to date and its components are testable and so it will serve as our guide in the formulation of specific questions related to visceral pain. The first component of this model is a synthesis of Ruch's convergence-projectioa theory and MacKenzie's convergence-facilitation theory and describes the referral of visceral pain to somatic structures. The second component of this model describes the phenomenon of somatic tissue hyperalgesia that occurs in association with visceral pain and which is best explained by peripheralist theories. Visceral pain is encoded in the activity of dorsal horn neurons activated directly by visceral and somatic primary afferents and also indirectly via recurrent modulatory neuronal loops involving both spinal and brain-stem components. The activity of dorsal horn neurons in response to a noxious visceral stimulus is a function of the number of sensory afferents to the spinal cord activated by that stimulus, the frequency and duration of the activity of these afferents, and the basal excitability of the neurons receiving this input. The activity of the afferents to the spinal cord and the excitability of dorsal horn neurons receiving visceral input are increased with repeated or persistent (pathological) noxious visceral stimuli due (1) to a sensitization of afferents which occurs secondary to local mechanisms in the viscera (e.g., chemical mediators related to tissue damage and/or ischemia) and (2) to a facilitation of dorsal horn neuronal responses which occurs via central mechanisms identical to those observed by Woolf and associates [e.g., 491] in response to deep tissue afferent inputs. The degree of facilitation is dependent on the immediately preceding activity in the afferents since a critical level of afferent activity is required before the mechanisms of facilitation come into play. Hence, visceral pain does not occur in response to localized or brief stimuli because the activity of dorsal horn neurons encoding visceral nociception is due to more than the spatial and simple temporal summation of polymodal visceral afferent activity. In most cases, visceral pain is dependent on the sensitization of afferent inputs and a facilitation of dorsal horn neurons to these afferent inputs; both sensitiza-
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tion and facilitation take time to become estabfished and both outlast the stimulus. If a sufficiently large area of visceral tissue is stimulated intensely enough, pain may be sensed prior to the development of sensitization or facilitation, but this typically is not the case. The referral of visceral pain to somatic structures is due to viscerosomatic convergence onto at least 2 main classes of spinal neurons receiving afferent inputs from all deep tissues represented at a particular spinal segment: one group of these neurons is involved in the localization Gf pain and projects to the brain while at least one other group of neurons has short ascending projections and/or long ascending projections with collaterals projecting into multiple spinal segments. Initially, visceral pain is poorly localized, dull and achy due to the wide divergence of visceral afferents in the spinal cord. In comparison with the surface of the body, the viscera are sparsely innervated by afferents to the spinal cord. Individual visceral afferents weakly activa~ .~econd-order spinal neurons in numerous spinal segments, some relatively distant. Primary afferents from cutaneous structures do not diverge as widely within the spinal cord and, moreover, there exist somatic primary afferents which are nociceptive specific. The stimulation of only a few of these cutaneous afferents results in a high level of excitation of relatively few dorsal horn neurons, resulting in the consequent well-localized pain. Activity in cutaneous afferents does not facilitate responses of dorsal horn neurons in the same way as deep tissue afferents. Poorly localized visceral pain becomes better localized as visceral afferent input increases due to the process of facilitation and/or activation of specific or 'silent' nociceptors. The greatest localization occurs when somatic structures (e.g., parietes) become involved in the painproducing process (e.g., with spread of infection). The hyperalgesia in cutaneous and deep tissues that occurs in association with visceral pain is a combination of increased sympathetic outflow, due primarily to direct visceral affere~ connections in the prespinal ganglia, and secondarily to axon reflexes arising in axonal extensions to both visceral and somatic structures. Manipulations which produce pain relief in conditions such as
reverse sympathetic dystrophy syndrome will lead to relief of the somatic hyperalgesia associated with visceral pa~n. This is an admittedly and purposely speculative model of visceral pain, but it has some support from the scientific and clinical literature. Studies to date have been predominantly descriptive and only a few, such as those using analgetic drugs, are truly experimental in that a hypothesis was proposed and specific endpoints measured. This model of visceral pain is presented so that specific questions can be asked by ourselves and others to address quantitatively whether there is support for these speculations.
Directions for research As stated earlier, experimental investigations of visceral pain have addressed 5 main topics: the nature of the adequate stimulus for pain production, the site of its action, the distribution of pain nerve endings in the viscera, the peripheral and central pathways which lead from viscus to sensorium, and the mechanisms involved in the localization of visceral pain. To date, none of these aspects of visceral pain has been definitively characterized. Numerous qualitative studies have identified probable components of visceral pain processing, but pending quantitative analysis by experimental studies, particularly psychophysiological studies, limited progress will be made towards a scientifically based cnderStandmg of visceral pain or the rational development of new therapies to treat it. Subjective generalities and anecdotal examples are, and always have been, of limited scientific value. Strict definitions of both stimuli and responses to those stimuli are required. The literature reviewed here contains numerous examples where the term 'response' was never defined and in many studies 'responsive units' were grouped as though functionally the same, despite tl~e demonstration that individual units in some reports had opposite responses to a given visceral stimulus. Even when 'defined,' criteria for 'response' included such characterizations as 'looking like a response.' Simple qualitative descriptions of neuronal, reflex and behavioral responses to visceral stimuli have been useful as they have idcr,:ified
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generalities of visceral sensation tha~ now need to be investigated more rigorously. In the hope of facilitating the process of scientific definition of visceral pain, we propose the following criteria as necessary for a valid, adequate, noxious, visceral stimulus: (1) the stimulus must produce pain in humans experimentally and ideally be related to p~.thological pain; (2) the stimulus must alter the behavior of the experimen-. tal subject in a way consistent with an interpretation that the stimulus is aversive (i.e., the animal changes behavior to avoid the onset or continuation of the stimulus); (3) the stimulus must evoke basic physiological 'pseudoaffective' reflexes consistent with what occurs in humans in response to visceral pain; and (4) responses to the stimulus must be modulated by antinociceptive manipulations (e.g., morphine) in a way consistent with the clinical effects of the same manipulations in humans experiencing visceral pain. These criteria obviously emphasize that animal models must closely mimic the human situation and are simple extensions of previously accepted criteria for noxious stimuli stated at the beginning of this review. However, the criteria listed above require experimental proofs and are testable. Stimuli used in experimental studies of visceral pain also should be controllable, quantifiable, reproducible and, ideally, graded. Responses to these stimuli should be reliable and, following characterization, predictable, although not necessarily identical from trial to trial. If responses are not reliable, studies of their modulation are of little value scientifically since it is unclear what is being examined, modulation or the unreliability of responses. Thus, if the neuronal substrates of visceral sensation are to be understood based on the study and characterization of responses (in order to make comparisons with complimenta~ ps:~chophysiological studies in humans), then the stimuli used to activate these neurons must be reproducible and the responses as reliable and predictable as are human responses to the same stimuli.
Acknowledgements The authors gratefully acknowledge the graphics
produced by Mike Burcham, the secretarial assistance of Kathryn Renbarger and Marilynn Kirkpatrick and the critical comments or, earlier versions of this essay by Jayne Ness. The authors have been supported by DHHS Awards NS 19912, NS 24598, H L 32295, DA 02879, a Life and Health Insurance Medical Research Fellowship (T.J.N.) and an unrestricted Pain Research Grant from Bristol-Myers Squibb. References 1 Aars, H. and Akre, S., Reflex changes in sympathetic activity and arterial blood pressureevoked by afferent stimulation of the renal nerve, Acta Physiol. Scand., 78 (1970) 184-188. 2 Abrahams, V.C. and Swett, J.E., The pattern of spinal and medullary projections from a cutaneous nerve and a muscle nerve of the forelimb of the cat: a study using the transganglionic transport of HRP, J. Comp. Neurol., 246 (1986) 70-84. 3 AbeUi, L., Conte, B., Somme, V., Maggi, C.A., Girliani, S. and Meli, A., A method for studying pain arising from the urinary bladder in conscious, freely-moving rats, J. Uroi., 141 (1989) 148-151. 4 Acheson, G.H., Rosenblueth, A. and Partington, P.F., Some afferent nerves producing reflex responses of the nictitating membrane, Am..I. Physiol., 115 (1936) 316-320. 5 Aidar, O., Geohogan, W.A. and Ungewitter, L.H., Splanchnic afferent pathways in the central nervous system, J. Neurophysiol., 15 (1952) 131-138. 6 Akeyson, E.W. and Schramm, L.P.. Viscerosomatic convergence at two levels of the rat spinal cord, Neurosci. Abst., 14 (1988) 727. 7 Albano, J.-P. and Gamier, L., Buibo-spinal respiratory effects originating from the splanchnic afferents, Resp. Physiol., 51 (1983) 229-239. 8 Alderman, A.M. and Downman, C.B.B., Reflex activation of intercostal nerves and trunk muscles by non-myelinated fibres of the splanchnic nerve in rabbits, J. Physiol. (Lond.), 150 (1960) 463-477. 9 Alexander, W.F., The innervation of the biliary system, J. Comp. Neurol., 72 (1940) 357-369. 10 Alexander, W.F., M,~,:Lcod, A.G. and Barker, P.S., Sensibility of the exposed human heart and pericardium, Arch. Surg., 19 (1929) 1470-1483. 11 AI!es, A. and Dora, R.M., Peripheral sensory nerve fibers that dichotomize to supply the brachium and the pericardium in the rat: a possible morphological explanation for referred cardiac pain, Brain Res., 342 (1985) 382-385. 12 Amassian, V.E., Cortical representation of visceral afferents, J. Neurophysiol., 14 (1951) 434-444. 13 Amassian, V.E., Fiber groups and spinal pathways of cortically represented visceral afferents, J. Neurophysiol., 14 (1951) 445-460.
219 14 Ammons, W.S., Renal afferent input to thoracolumbar spinal neurons of the cat, Am. J. Physiol., 250 (1986) R435-R443. 15 Ammons, W.S., Characteristics of spinoreticular and spinothalamic neurons with renal input, J. Neu~-ophysiol., 58 (1987) 480-495. 16 Ammons, W.S., Spinoreticular cell responses to renal venous and ureteral occlusion, Am. J. Physiol., 254 (1988) R268-R276. 16a Ammons, W.S., Spinoreticular cell responses to intrarenal injections of bradykinin, Am. J. Physiol., 255 (1989) R994-R1001. 17a Ammons, W.S., Renal and somatic input to spinal neurons antidromically activated from the ventrolateral medulla, J. Neurophysiol., 60 (1988) 1967-1981. 17b Ammons, W.S., Electrophysiological characteristics of primate spinothalamic neurons with renal and somatic inputs, J. Neurophysiol., 61 (1989) 1121-1130. 17c Ammons, W.S., Primate spinothalamic cell responses to ureteral occlusion, Brain Res., 496 (1989) 124-130. 17d Ammons, W.S., Responses of primate spinothalamic tract neurons to renal pelvic distension, J. Neurophysiol., 62 (1989) 778-788. 18 Ammons, W.S., Blair, R.W. and Foreman, R.D., Vagal afferent inhibition of spinothalamic cell responses to sympathetic afferents and bradykinin in the monkey, Circ. Res., 53 (1983) 603-612. 19 Ammons, W.S., Blair, R.W. and Foreman, R.D., Vagal afferent inhibition of primate thoracic spinothalamic neurons, J. Neurophysiol., 50 (1983) 926-940. 20 Ammons, W.S., Blair, R.W. and Foreman, R.D., Responses of primate T1-T5 spinothalamic neurons to gall bladder distension, Am. J. Physiol., 247 (1984) R995R1002. 21 Ammons, W.S., Blair, R.W. and Foreman, R.D., Greater splanchnic excitation of primate T1-T5 spinothalamic neurons, J. Neurophysiol., 51 (1984) 592-603. 22 Ammons, W.S., Blair, R.W. and Foreman, R.D., Raphe magnus inhibition of primate T1-T4 spinothalamic cells with cardiopulmonary visceral input, Pain, 20 (1984) 247260. 23 Ammons, W.S. and Foreman, R.D., Cardiovascular and T2-T4 dorsal horn cell responses to gallbladder distention in the cat, Brain Res., 321 (1984) 267-277. 24 Ammons, W.S. and Foreman, R.D., Responses of T2-T4 spinal neurons to stimulation of the greater splanchnic nerves of the cat, Exp. Neurol., 83 (1984) 288-301. 25 Ammons, W.S., Girardot, M.N. and Foreman, R.D., Effects of intracardiac bradykinin on T2-T5 medial spinothalamic cells, Am. J. Physiol., 249 (1985) 147-152. 26 AwJnons, W.S~, Girardot, M.N. and Foreman, R.D., T2T5 spinothalamic neurons projecting to medial thalamus with viscerosomatic input, J. Neurophysiel., 54 (1985) 73-89. 27 Ammonia, W.S., Girardot, M.N. and Foreman, R.D., Periventric~dar gray inhibition of thoracic spinothalamic cells
projecting to medial and lateral thalamus, J. Neurophysiol., 55 (1986) 1091-1103. 27a Ammons, W.S. and Sinha, R., Responses of thoracolumbar spinal neurons to renal artery occlus~ion, Am. J. Physiol., 256 (1989) H1515-H1523. 28 Andrews, C.J.H., Andrews, W.H.H. and Orbach, J., A sympathetic reflex elicited by distension of the mesenteric venous bed, J. Physiol. (Lond.), 226 (1972) 119-131. 29 Andrews, P.L.R., Vagal afferent innervafion of the gastrointestinal tract. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 65-86. 30 Applebaum, A.E., Vance, W.H. and Coggeshall, R.E., Segmental localization of sensory cells that innervate the bladder, J. Comp. Neurol., 192 (1980) 203-209. 31 Armstrong, D., Dry, R.M.L., Keele, C.A. and Markham, J.W., Observations on chemical excitants of cutaneous pain in man, J. Physiol. (Lond.), 120 (1953) 326-351. 32 Armstrong, D., Jepson, J.B., Keele, C.A. and Stewart, J.W., Pain producing substance in human inflammatory exudates and plasma, J. Physiol. (Lond.), 135 (1957) 350370. 33 Ashkenaz, D.M., An experimental analysis of centripetal visceral pathways based on the visceropannicular reflex, Am. ~. Physiol., 120 (1937) 587-596. 34 Ashkenaz, D.M. and Spiegel, E.A., The viscero-parmicular reflex, Am. J. Physiol., 112 (1935) 573-576. 35 Ashton, J.H., lwamoto, G.A., Longhurst, J.C. and Mitchell, J.H., Reflex cardiovascular depression induced by capsaicin injection into canine liver, Am. J. Physiol., 242 (1982) H955-H960. 36 Bahr, R., Blumberg, H. and J~nig, W., Do dichotomizing fibers exist wi~h s~pply visceral organs as well as som~ ~ie structures? A contribution to the problem of referred pain, Neurosci. Left., 24 (1981) 25-28. 37 Bain, W.A., Irving, J.T. and McSwiney, B.A., The afferent fibers from the abdomen in the splancl,-iic nerves, J. Physiol. (Lond.), 84 (1935) 323-333. 38 Baker, D.G., Coleridge, H.M, Coleridge, J.C.G. and Nerdrum, T., Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat, J. Physiol. (Lond.), 306 (1980) 519536. 39 Bardos, G. and Ado.m, G., Visceroceptive control of operant behavior in rats, Physiol. Behav., 20 (1978) 369-375. 40 Bardos, G., Nagy, J. and Adam, G., Thresholds of behavioral reactions evoked by intestinal and skin stimuli in rats, Physiol. Behav., 24 (1980) 661-665. 41 Barish, C.F., Castell, D.O. and Richter, J.E., Graded esophageal balloon distension: a new provocative test for noncardiac chest pain, Dig. Dis. Sci., 31.(198o) 1292-1298. 42 Barja, F. and Mafllison, R., Sensory irmewation of the rat portal vein and the hepatic artery, J. Auton. Nerv. Syst., 10 (1984) 117-125. 43 Baron, R., J~.nig, W. and McLacldan, E.M., The afferent and sympathetic components of the lumbar spinal outflow
220
44
45
46
47 48
49
50
51
52
53
54
55
56
57
58
59
60
to the colon and pelvic organs in the cat. I. The hypogastric nerve, J. Comp. Neurol., 238 (1985) 135-146. Baron, R., J~tig, W. and McLachlan, E.M., The 'afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. II. The lumbar splanchnic nerves, J. Comp. Neurol., 238 (1985) 147-157. Baron, R., J~mig, W. and McLachlan, E.M., The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. III. The colonic nerves, incorporating an analysis of all components of the lumbar prevertebral outflow, J. Comp. Neurol., 238 (1985) 158-168. Bayliss, J.H., Kauntze, R. and Trounce, J.R., Observations on distension of the lower end of the esophagus, Quart. J. Med., 24 (1955) 143-153. Bean, J.W., Intestines in reflex chemical control of breathing, Am. J. Physiol., 171 (1952) 522-527. Bentley, F.H. and Smithwick, R.H., Viscer~ pah'~ produced by balloon distension of the jejunum, Lancet, i-ii (1940) 389-391. Berldey, K.J., Robbins, A. and Sato, Y., Afferent fibers supplying the uterus in the r~t, J. Neurophysiol., 59 (1988) 142-163. Berkley, K.J., Robbins, A. and .Sato, Y., Sensory input from contractions of the uterus in the rat, Neurosci. Abst., 14 (1988) 727. Bernstein, L.M., Fruin, R.C. and Pacini, R., Differentiation of esophageal pain from angina pectoris: role of the esophageal acid perfusion test, Medicine, 41 (1962) 143162. Bettman, R.B. and Rubinfeld, S.H., Gallbladder-heart reflexes in man under spinal anesthesia, Am. Heart J., 10 (1935) 550-552. Blair, R.W., Noxious cardiac input onto neurons in medullary reticular formation, Brain Res., 326 (1985) 335-346. Blair, R.W., Cardiac input to medullary reticular formation: neuronal respo.-ses to CAO, Am. J. Physiol., 251 (1986) R670-R679. Blair, R.W., Cardiac input to medullary reticular formation: neuronal responses to mechanical stimuli, Am. J. Physiol., 251 (1986) R680-R689. Blair, R.W., Responses of feline medial medullary reticulospinal neurons to cardiac input, J. Neurophysiol., 58 (1987) 1149-1167. Blair, R.W. and Foreman, R.D., Activation of feline spinal neurons by potentiated ventricular contractions and other mechanical cardiac stimuli, J. Physiol. (Lond.), 404 (1988) 649-667. Blair, R.W., Ammons, W.S. and Foreman, R.D., Responses of thoracic spinothalamic and spinoreticular cells to coronary artery occlusion, J. Neurophysiol., 51 (1984) 636-648. Blair, R.W., Weber, R.N. and Foreman, R.D., Characteristics of primate spinothalamic tract neurons receiving viscerosomatic convergent inputs in T3-T5 segments, J. Neurophysiol., 46 (1981) 797-811. Blair, R.W., Weber, R.N. and Foreman, R.D., Responses
of thoracic spinothalamie neurons to intracardiac injections of bradykinin in the monkey, Circ. Res., 51 (1982) 83-94. 61 Blair, R.W., Weber, R.N. and Foreman, R.D., Responses of thoracic spinoreticular and spinothalamic cells to intracardiac bradykinin, Am. J. Physiol., 246 (1984) H500H507. 62 Block, A.J., Feinberg, H., Herba~ynska-Ccdro, K. and Vane, J.R., Anoxia and induced release of prostaflandins in rabbit isolated hearts, Circ. Res., 36 (1975) 34-42. 63 Bloomfield, A.L. and Polland, W.S., Experimental referred pain from the gastro-intestinal tract. II. Stomach, duodenum and colon, Jo Cliff. Invest., 10 (1931) 453-473. 64 Blumberg, B., Haupt, P., J~nig, W. and KShler, W., Encoding of visceral noxious stimuli in the discharge patterns of visceral afferent fibres from the colon, Pfliigers Arch., 398 (1983) 33-40. 65 Boley, S.J., Agrawal, G.P., Warren, A.R., Veith, F.J., Levowitz, B.S., ]reiber, W., Dougherty, J., Schwartz, S.S. and Gfiedman, M.L., Pathophysiologic effects of bowel distention on intestinal blood flow, Am. J. Surg., 117 (1969) 228-234. 66 Boyden, E.A. and Rifler, L.G., Localization of pain accompanying faradiz~tion of stomach and duodenum in healthy individuals, J. Clin. Invest., 13 (1934) 833-851. 67 Brasch, H. and Zetler, G., Caerulein and morphine in a model of visceral pain: effects on the hypotensive reponse to renal pelvis distension in the rat, Naunyn-Schmiedeberg's Arch. Pharmacol., 319 (1982) 161-167. 68 Brennan, T.J., Oh, U.T,, Girardot, M.-N., Ammons, W.S. and Foreman, R.D., Inhibition of cardiopulmonary input to thoracic spinothalamic tract cells by stimulation of the subcoeruleus-parabrachial region in the primate, J. Auton. Nerv, Syst., 18 (1987) 61-72. 69 Brennan, T.J., Oh, U.T., Hobbs, S.F., Garrison, D.W. and Foreman, R.D., Urinary bladder and hindlimb afferent input inhibits activity of primate T2-T5 spinothalamic tract neurons, J. Ncurophysiol., 61 (1989) 573-588. 70 Brown, A.M., Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischemia, J. Physiol. (Lond.), 190 (1967) 35-53. 71 Brown, A.M. and Malliani, A., Spinal sympathetic reflexes initiated by coronary receptors, J. Physiol. (Lond.), 212 (1971) 685-705. 71a Brown, S.T., Campbell, D. and Kurtz, A., Characteristics of labor pain at two stages of cervical dilation, Pain, 38 (1989) 289-295. 72 Burch, G.E. and DePasquale, N.P., Bradykinin, digital blood flow, and the arteriovenous anastamoses, Circ. Res., 10 (1962) 105-115. 73 Cadden, S.W. and blorrison, J.F.B., The effects of visceral distension on the activities of lumbar dorsal horn neutones in the rat, J. Physiol. (Lond.), 350 (1984) 71P. 74 Calaresu, F.R., Stella, A. and Zanchetti, A., Haemodynamic responses and renin release during stimulation of afferent renal nerve in the cat, J. Physiol. (Lond.), 255 (1976) 687-700. 75 Calaresu, F.R., Tobey, J.C., Heidemann, S.R. and Weaver,
221 L., Splenic and ren~! sympathetic responses to stimulation of splenic receptors in cats, Am. J. Physiol., 247 (1984) R856-R865. 76 Calvino, B., Villanueva. L. and Le Bars, D., The heterotopic effects of visceral pain: behavioural and electrophysiological approaches in the rat, Pain~ 20 (1984) 261-271. 77 Cannon, B., A method of stimulating autonomic nerves in the unanesthetized cat with observation on the motor and sensory effects, Am. J. Physiol., 105 (1933) 366-372. 78 Capps, J.A. and Coleman, G.H., Experimental observation on the localization of the pain sense in the parietal and diaphragmatic peritoneum, Arch. Intern. Med., 30 (1922) 778-789. 79 Caprilli, R., Capurso, L. e Paolu~, P., Studio de~ dolore da distensione delrileo e del crasso nelruomo, Arch. Ital. Mal. Appar. Dig., 34 (1967) 268-278. 80 Carlson, A.J. and Braafladt, L.H., Contributions to the physiology of the stomach, Am. J. Physiol., 36 (1915) 153-170. 81 Carlson, A.J. and Luckhardt, A.B., Studies on the visceral sensory nervous system. V. Cardiac and vasomotor reflexes induced by visceral stimulation in amphibia and reptilia, Am. J. Physiol., 55 (1921) 31-52. 82 Carstens, E. and Yokota, T., Viscerosomatic convergence and responses to intestinal distension of neurons at the junction of midbrain and posterior thalamus in the cat, Exp. Neurol., 70 (1980) 392-402. 83 Ca.~ati, R., Lombardi, F. and Malliani, A., Afferent sympataet~c unmyelinated fibres g~th left ventricular endings in cats, J. Physiol. (Lond.), 292 (1979) 135-148. 84 Cassidy, S.S., Ashton, J.H., Wead, W.B., Kaufman, M.P., Monsereenusorn, Y. and Whiteside, J.A., Reflex cardiovascular responses caused by stimulation of pulmonary C-fibers with capsaicin in dogs, J. Appl. Physiol., 60 (1986) 949-958. 85 Cechetto, D.F. and Saper, C.B., Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat, J. Comp. Neurol., 262 (1987) 27-45. 86 Cervero, F., Noxious intensities of visceral stimulation art~ required to activate viscerosomatic multireceptive neurons in the thoracic spinal cord of the cat, Brain Res., 240 (1982) 350-352. 87 Cervero, F., Afferent activity evoked by natural stimulation of the bifiary system in the ferret, Pain, 13 (1982) 137-151. 88 Cervero, F., Supraspinal connections of neurones in the thoracic spinal cord of the cat: ascending projections and effects of descending impulses, Brain Res., 275 (1983) 251-261. 89 Cervero, F., Somatic and visceral inputs to the thoracic spinal cord of the cat: effects of noxious stimulation of the biliary system, J. Physiol. (Lond.), 337 (1983) 51-67. 90 Cervero, F., Fine afferent fibres from viscera and visceral pain: anatomy and physiology of viscero-somatic convergence. In: R.F. Sclunidt, H.G. Schaible and C. Vahle-Hinz (Eds.), Fine Afferent Nerve Fibers and Pain, VCH, Weinheim, 1987, pp. 322-331. 91 Cervero, F. and Connell, L.A., Distribution of somatic
and visceral primary afferent fibres within the thoracic spinal cord o¢ ~he cat, J. Comp. Neurol., 230 (1984) 88-98. 92 Cervero, F., Connell, L.A. and Lawson, S.N., Somatic and visceral primary afferents in the lower thoracic dorsal root ganglia of the cat, J. Comp. Neurol., 228 (1984) 422-431. 93 Cervero, F. and Iggo, A., Natural stimulation of urinary bladder afferents does not affect transmission through hmbosacral spinocervical tract neurones in the cat, Brain Res., 156 (1978) 375-379. 94 Cetvero, F. and Lumb, B.M., Bilaterai inputs and supraspinal control of viscerosomatic neurones in the lower thoracic cord of the cat, J. Physiol. (Lond.), 403 (1988) 221-237. 95 Cervero, F., Lumb, B.M. and Tattersall, J.E.H., Supraspihal loops that mediate visceral inputs to thoracic spina: cord neurones in the cat: involvement of descending pathways from raphe and reticular formation, Neurosci. Lett., 56 (1985) 189-194. 96 Cervero, F. and Tattersall, J.E.H., Cutaneous receptive fields of somatic and viscerosomatic neurones in the thoracic spinal cord of the cat, J. Comp. Neurol., 237 t l o ~ -~'~ _3~t2 97 Cervero, F. and Tattersall, J.E.H., Somatic and visceral sensory integration in the thoracic spinal cord. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 189-206. 98 Cervero, F. and T~ttersall, J.E.H., Somatic and visceral inputs to the thoracic spinal cord of the cat: marginal zone (lamina I) of the dorsal horn, J. Physiol. (Lond.), 388 (1987) 383-395. 99 Chandler, M.J., Garrison, D.W., Brennan, T.J. and Foreman, R.D., Effects of chemical and electrical stimulation of the midbrain on feline T2-T6 spinoreticular and spinal cell activity evoked by cardiopulmonary afferent input, Brain Res., 496 (1989) 148-164. 100 Chapman, C.D, Ammons, W.S. and Foreman, R.D., Raph¢ magnus inhibition of feline T1-T4 spinoreticular tract cell responses to visceral and somatic inputs, .I. Neurophysio,~., 53 (1985) 773-785. 101 Chapman, W.P., Herrera, R. and Jones, C.M., A comparison of pain produced experimentally in lower esophagus, common bile duct, and upper small intestine with pain experienced by patients with diseases of biliary tract and pancreas, Surg. Gynecol. Obstet., 89 (1949) 573-582. 102 Chapman, W.P. and Jones, C.M., Variations in cutaneous and visceral pain sensitivity in normal subjects, J. Chn. Invest., 23 (1944) 81-91. 103 Ciriello, J. and Calaresu, F.R., Central projections of afferent renal fibers in the rat: an anterograde transport study of horseradish peroxidase, J. Auton. Nerv. Syst., 8 (1983) 273-285. 104 Clark, S.J. and Smith, T.W., Opiate-induced inhibition of the visceral distension reflex by peripheral and central mechanisms, Naunyn-Schmiedeberg's Arch. Pharmacol., 330 (1985) 179-183. 103 Clelland, J.G.P. and Tait, J., Nervous connections of the X4. j v , , , i
,,pau,,,,-
,..,
.
222 mammalian spleen, including an account of certain visceromotor and other abdominal reflexes, Quart. J. Exp. Physiol., 17 (1927) 179-204. 106 Clifton, G.L., Coggeshall, R.E., Vance, W.H. and Willis, W.D., Receptive fields of unmyelinated ventral root afferent fibres in the cat, J. Physiol. (Lond.), 256 (1976) 573600. 107 Clifton, G.L., Vance, W.H., Applebaum, K.L., Coggeshall, R.E. m~d Willis, W.D., Responses of unmyelmated afferents in the mammalian ventral root, Brain Res., 82 (1974) 163-167. 108 Coffman, J.D., The effect of aspirin on pain and hand blood flow responses to intra-arterial injection of bradykinin, Clin. Pharmacol. Ther., 7 (1966) 26-37. 109 Coggeshall, R.E. and Ito, H., Sensory fibres in ventral roots L7 ar.~ $1 in the cat, J. Physiol. (Lond.), 267 (1977) 215-235. 110 Cohen, H., Visceral pain, Lancet, ii (1947) 6487-6489. 111 Colburn, R.W., Coombs, D.W., Degnen, C.C. and Rogers, L.L., Mechanical visceral pain model: chronic intermittent intestinal distension in the rat, Physiol. Behav., 45 (1989) 191-197. 112 Coombs, D.W., Rogers, L.L., Raye, K.N. and Addis, M., Dose-response of intrathecal clonidine in the rat mechanical visceral pain model, Neurosci. Abst., 14 (1988) 175. 113 Cormia, F.E. and Dougherty, J.W., Proteolytic activity in development of pain and itching, J. Invest. Dermatol., 35 (1960) 21-26. 114 Craig, A.D. and Mense, S., The distribution of afferent fibers from the gastrocnemius-soleus muscle in the dorsal horn of the cat as revealed by the transport of horseradish peroxidase, Neurosci. Lett., 41 (1983) 233-238. 115 Cross, B.A., The motility and reactivity of the oestrogenized rabbit uterus in vivo; with comparative observations on milk ejection, J. Endocrinol., 16 (1958) 237-260. 116 Crousillat. J., Ranieri, F., Mei, N. et Aubert, M., Effets de la stimulation des fibres et des mt~cia,'mor6cepteurs splanehnique ~ur l'acfivit6 unitaJrc du co~'tex ~,omatique, Pfltigers Arch., 348 (1974) 127-137. 117 Crowley, R.T., Reflex modification of respiration by intestinal distentionl Am. J. Physiol., 133 (1941) 253-254. 118 Csendes, A. and Sepulveda, A., lntraluminal gallbladder pressure measurements in patients with chronic or acute cholecystitis, Am. J. Surg., 139 (1980) 383-384. 119 Cuilen, M.L. and Reese, H.L., Myocardial circulatory changes measured by clearance of Na 2'* - effect of common duct distension on myocardial circulation, J. Appl. Physiol., 5 (1952) 281-284. 120 Cunningham D.J.C., Guttmann, L., Whitteridge, D. and Wyndham, C.L., Cardiovascular response to bladder distension in paraplegic patients, J. Physiol. (Lond.), 121 (1953) 581-592. 121 Dalsgaard, C.-J. and Lundberg, J.M, Evidence for a spinal afferent innervation of the guinea pig lower respiratory tract as stud~ed by the horseradish peroxidase technique, Neurosci. Lett., 45 (1984) 117-122. 122 Dalsgaard, C.-J. and Ygge, J., Separate populations of
primary sensory neurons project to the splanchnic nerve and thoracic spinal nerve rami of the rat. A fluorescent double-labelling study, Med. Biol., 63 (1985) 88-91. 123 Danzebrink, R.M., and Gebhart, G.F., Visceral nociception: inhibition by spinal a2-adrenoceptors, Neurosci. Abst., 14 (1988) 851. 124 Davis, K.D. and Dostrovsky, J.O., Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation, Pain, 25 (1986) 395-401. 125 Davis, L., The pathway for visceral afferent impulses within the spinal cord, Am. J. Physiol., 59 (1922) 381-393. 126 Davis, L., Hart., J.T. and Crain, R.C., The pathway for viscer-d afferent impulses within the spinal cord, Surg. Gyn~col. Obstet., 48 (1929) 647-651. 127 Davis, L. and Pollock, L.J., The peripheral pathway for painful sensatior.s, Arch. Neuro!. Psychiat., 24 (1930) 883-898. 128 Davis, L., Pollock:. L.J. and Stone, T.T., Visceral pain, Surg. Gynecol. O~stet., 55 (1932) 418-427. 129 DeGroat, W.C., lahibition and excitation of sacral parasympathetic neurons by visceral and cutaneous stimuli in the cat, Brain Res., 33 (1971) 499-503. 130 DeGroat, W.C., Spinal cord projections and neuropeptides in visceral afferent neurons. In: F. Cerver¢ and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 165-187. 131 DeGroat, W.C., Neuropeptides in pelvic afferent pathways, Experientia, 43 (1987) 801-813. 132 DeGroat, W.C., Booth, A.M., Milne, R.J. and Roppolo, J.R., Parasympathetic preganglionic neurons in the sacral spinal cord, J. Auton. Nerv. Syst., 5 (1982) 23-43. 133 DeGroat, W.C., Nadelhaft, I., Milne, R.J., Booth, A.M.. Morgan, C. and Thor, K., Organization of the sacral parasyrogathetic reflex pathways to the urinary bladder and large intestine, J. Auton. Nerv. Syst., 3 (1981) 135-160. 133a DeLeo, J.A., Colburn, R.W., Coombs, D.W. and Ellis, M.A., The differentiation of NSAIDS and prostaglandin action using a mechanical visceral pain model in the rat, Pharmaeol. Biochem. Behav., 33 (1989) 253-255. 134 Denny-Brown, D. and Robe,'tson, E.G., On the physiology of micturition, Brain, 56 (1933) 149-190. 135 Deraedt, R., Jouquey, S., Deleval6e, F. and Flahaut, M., Release of prostaglandins E and F in an algogenic reaction and its inhibition, Eur. J. Pharmacol., 61 (1980) 17-24. 136 Devroede, G., Vobecky, S., Masse, S., Arhan, P., Leger, C., Duguay, C. and Hemond, M., Ischemic fecal incontinence and rectal angina, Gastroenterology, 83 (1982) 970980. 137 Dickerson, G.D., Engle. R.J., Guzman, F., Rodgers, D.W. and Lira, R.K.S., The intraperitoneal bradykinin-evoked pain (BK-EP) test for analgesia, Life Sei., 4 (1965) 20632069. 138 Dockray, G.J. and Sharkey, K.A., Neurochemistry of viscer~ afferent neurons, in: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 133-148.
223 138a Doerffler-Melly, J. and Neuhuber, W.L., Rectospinai neurons: evidence for a direct projeca~a from the enteric to the central nervous system in the rat, Neurosci. Lett., 92 (1988) 121-125. 139 Donovan, M.K., Wyss, J.M. and Wintemitz, S.R., Localization of renal sensory neurons using the fluorescent dye technique, Brain Res., 259 (1983) 119-122. 140 Doran, F.S.A., The sites to which pain is referred from the con~non bile duct in man and its impfication for the theory of referred pain, Br. J. Surg., 54 (1967) 599-606. 141 Doran, F.S.A. and Ratcliffe, A.H., The physiological mechanism of referred shoulder-tip pain, Brain, 77 (1954) 427-434. 142 Downie, J.W., Champion, J.A. and Nance, D.M., A quantitative analysis of the afferent and extrinsic efferent innervation of specific regions of the bladder and urethra in the cat, Brain Res. Bull., 12 (1984) 735-740. 143 Downman, C.B.B., Cerebral destination of splanchnic afferent impulses, J. Physiol. (Lond.), 113 (1951) 434-441. 144 Downman, C.B.B., Skeletal muscle reflexes of splanchnic and intercostal nerve origin in acute spinal and decerebrate cats, J. Neurophysiol., 18 (1955) 217-235. 145 Downman, C.B.B. and Evans, M.H., The distribution of splanclmic afferents in the spinal cord of cat, J. Physiol. ~Lond.), 137 (1957) 66-79. 146 Downman, C.B.B. and McSwiney, B.A., Reflexes elicited by visceral stimulation in the acute spinal animal, J. Physiol. (Lond.), 105 (1946) 80-94. 147 Downman, C.B.B., McSwiney, B.A. and Vass, C.C.N., Sensitivity of the small intestine, J. Physiol. (Lond.), 107 (1948) 97-106. 148 Dray, A. and Nunan, L., Opioid inhibition of reflex urinary bladder contractions: dissociation of supraspinal and spinal mechanisms, Brain Res., 337 (1985) 142-145. 149 Dworken, H.J., Biel, F.J. and Machella, T.E., Supradiaphragmatic reference of pait~ ¢ro~ :he ~olo-, Gastroen,,~rology, 22 (!952) 222--229. 150 Edgeworth, F.H., On a large-fibred sensory supply of the thoracic and abdominal viscera, J. Physiol. (Lond.), 13 (1892) 260-271. 151 Elam, M., Thoren, P. and Svensson, T.H., Locus coeruleus neurons and sympathetic nerves: activation by visceral afferents, Brain Res., 375 (1986) 117-125. 152 Ellison, J.P. and Clark, G.M., Relxograde axonal transport of horseradish peroxidase in peripheral autonomic nerves, J. Comp. Neurol., 161 (1974)~03-114. 153 EIfvin, L.G. and Dalsgaard, C.J., Retrograde axonal transport of horseradish peroxidase in afferent fibers of the inferior mesenteric ganglion of the guinea pig, Brain Res., 126 (1977) 149-153. 154 Evans, M.H. and McPherson, A., The effects of distension of the bladder on somatic reflexes in the cat, J. Physiol. (Lond.), 146 (1959) 448-458. 155 Farthing, M.J.G. and Lennard-Jones, J.E., Sensibility of the rectum to distension and the anorectal distension reflex in ulcerative colitis, Gut, 19 (1978) 64-69. 156 Felder, R.B. and Thames, M.D., Responses to activation
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
of cardiac sympathetic afferents with epicardial bradykinin, Am. J. Physiol., 242 (1982) 148-153. Felder, R.B. and Thames, M.D., The cardiocardiac sympathetic reflex during coronary occlusion in anesthetized dogs, Circ. Res., 48 (1981) 685-692. Fields, H.L., Meyer, G.A. and Partridge, Jr., L.D., Convergence of visceral and somatic input onto spinal neurons, Exp. Neurol., 26 (1970) 36-52. Fie~ds, I-I.L., Partridge, Jr., L.D. and Winter, D.L., Somatic and visceral receptive field properties of fibers in ventral quadrant white matter of the cat spinal cord, J. Neurophysiol., 33 (1970) 827-837. Fields, H.L. and Winter, D.L., Somatovisceral pathway: rapidly conducting fibers in the spinal cord, Science, 167 (1970) 1729-1730. Flower, R.J., Moncada, S. and Vane, J.R., Analgesic-antipyretics and anti-inflammatory agents and drugs employed in the treatment of gout. In" A.G. Gilman, L.S. Goodman, T.W. Rall and F. Murad (Eds.), Goodman and Gilman's Pharmacological Basis of Therapeutics, 7th edition, MacMillan, New York, 1985, pp. 674-715. Floyd, K., Hick, V.E., Koley, J. and Morrison, J.F.B., Effects of bradykinin mediated by autonomic efferent nerves, Quart. J. Exp. Physiol., 62 (1977) 11-17. Floyd, K., Hick, V.E., Koley, J. and Morrison, J.F.B., The effects of bradykinin on afferent units in intra-abdominal sympathetic nerve trunks, Quart. J. Exp. Physiol., 62 (1977) 19-25. Floyd, K., Hick, V.E. and Morrison, J.F.B., Mechanosensitive afferent units in the hypogastric nerve of the cat, J. Physiol. (Lond.), 259 (1976) 457-471. Floyd, K., Koley, J. and Morrison, J.F.B., Afferent discharges in the sacral ventral roots of cats, J. Physiol. (Lond.), 259 (1976) 37-38. Floyd, K. and Morrison, J.F.B., Splancbnic mechanoreceptors in the dog, Quart. J. Fxp. Physiol., 59 (1974) 361-366. Ford, G.T., Grant, D.A,, RJdeout, K.S., Davidson, J.S. and Wlfitelow, W.A., Inhibition of breathing associated with gall bladder stimulation in dogs, J. Appl. Physiol., 65 (1988) 72-79. Foreman, R.D., Viscerosomatic convergence onto spinal neurons responding to afferent fibers located in the inferior cardiac nerve, Brain Res., 137 (1977) 164-168. Foreman, R.D., Blair, R.W. and Weber, R.N., Vi~cerosomatic convergence onto T2-T4 spinoreticular, spinoreticular-spinothalamic, and spinothalamic tract neurons in the cat, Exp. Neurol., 85 (1984) 597-619. Foreman, R.D., Hancock, M.B. and Willis, W.D., Responses of spinothalamic tract cells in the thoracic spinal cord of the monkey to cutaneous and visceral inputs, Pain, 11 (1981) 149-162. Foreman, R.D. and Ohata, C.A., Effects of coronary artery occlusion on thoracic spinal neurons receiving viscerosomatic inputs, Am. J. Physiol., 238 (1980) H667H674. Foreman, R.D. and Weber, R.N., Responses from neurons
224 of the primate spinothalamic tract to electrical stimulation of afferents from the cardiopulmonary region and somatic structures, Brain Res., 186 (1980) 464-468. 173 Fox, R.H., Goldsmith, R., Kidd, D.J. and Lewis, G.P., Bradykinin as a vasodilator in man, J. Physiol. (Lond.), 157 (1961) 589-602. 174 Frank, M.H., Cardiovascular chemoreflexes from the perfused innervated ileum of the cat, Am. J. Physiol., 228 (1975) 944-953. 175 Fukuda, H. and Fukai, K., Postural change and straining induced by distension of the rectum, vagina and urinary bladder of decerebrate dogs, Brain Res., 380 (1986) 276286. 176 Fukuda, H. and Fukai, K., Ascending and descending pathways of reflex straining in the dog, Jpn. J. Physiol., 36 (19Rfi) 905-920. 177 Fukuda, H., Fukai, K., Yamane, M. and Okada, H., Pontine reticular unit responses to pelvic nerve and colonic mechanical stimulation in the dog, Brain Res., 207 (1981) 59-71. 178 Fukuda, H. and Koga, T., Midbrain stimulation inhibits the micturition, defecation and rhythmic straining reflexes elicited by activation of sacral vescical and rectal afferents in the dog, Brain Res., submitted. 179 Gaensler, E.A., Quantitative determination of the visceral pain threshold in man: charactenst|cs of visceral pain, effect of inflammation and analgesics on the threshold, and relationship of analgesia to visceral spasm, J. Clin. Invest., 30 (1951) 406-420. 180 Garrison, D.W., Chandler, M.J. and Foreman, R.D., Viscerosomatic convergence onto T2-T5 spinal cord dorsal horn cells from distal esophagus, heart and somatic fields in cat, Neurosci. Abst., 13 (1987) 582. 181 Garrison, D.W., Chandler, M.J. al~d Foreman, R.D, Responses of T2-T7 dorsal horn cells to distension of in. flamed and normal distal esophagus in cat, Neurosci. Abst., 14 (1Q88) 562. 182 Gernandt, B. and Zotterman, Y., Intestinal pain: an electrophysiological investigation on mesenteric nerves, Acta Physiol. Scand., 12 (1946) 56-72. 183 Giesler, Jr., G.J. and Liebeskind, .i.C., Ie~hibition of visceral pain by electrical stimulation of the periaqueductal gray matter, Pain, 2 (1976) 43-48. 184 Gilbert, N.C., Fenn, G.K. and LeRoy, G.V., The effect of distension of abdominal viscera on the coronary blood flow and on angina pectoris, JAMA, 115 (1940) 1962-1967. 185 Gilmore, J.P. and Tomomatsu, E., Renal mechanoreceptors in nonhuman primates, Am. J. Physiol., 248 (1985) R202-R207. 186 Giuliani, S., Maggi, C.A. and Meli, A., Capsaicin-sensitive afferents in the rat urinary bladder activate a spinal sympathetic cardiovascular reflex, Naunyn-Schmiedeberg's Arch. Fharmacoi., 338 (1988) 411-416. 1o7 Gokin, A.P., Synaptic activation of interneurons in the thoracic ~pinal cord by cutaneous, muscle and visceral afferents, Neurophysiology (Kiev), 2 (1970) 563-572.
188 Gokin, A.-P., Kostyuk, P.-G. and Preobrazhensky, N.-N., Neuronal mechanisms of interactions of high-threshold visceral and somatic afferent influences in spinal cord and medulla, J. Physiol. (Paris), 73 (1977) 319-333. 189 Goligher, J.C. and Hughes, E.S.R., Sensibility of the rectum and colon: its role in the mechanism of anal continence, Lancet, i-ii (1951) 543-548. 190 Gorman, A.J. and Zucker, I.H., Renal nerve and blood pressure responses to stimulation of cardiac receptors in dogs and cats by bradykinin, Basic Res. Cardiol., 79 (1984) 142-154. 191 Goshgarian, H.G. and Roubal, P.J., Origin and distribution of phrenic primary afferent nerve fibers in the spinal cord of the adt,,lt rat, Exp. Neurol., 92 (1986) 624-638. 191a Gottfried, S B. and DiMarco, A.F., Effect of intestinal afferent stimulation on pattern of respiratory muscle activation, J. Appl. Physiol., 66 (1989) 1455-1461. 192 Guilbaud, G., Benelli, G. and Besson, J.M., Responses of thoracic dorsal horn interneurons to cutaneous stimulation and to the administration of algogenic substances into the mesenteric artery in the spinal cat, Brain Res., 124 (1977) 437-448. 192a Gutterman, D.D., Pardubsky, P.D. and Gebhart, G.F., Attenuation of afferent spinal neuronal responses to successive coronary occlusions may contribute to silent ischemia, Circulation, 80 (1989) 552. 193 Guttmann, L. and Whitteridge, D., Effects of bladder distension on autonomic mechanisms after spinal cord injuries, Brain, 70 (1947) 361-404. 194 Guzman, F., Braun, C. and I,im, R.K.S., Visceral pain and the pseudaffective response to intra-arterial injection of bradykinin and other algesic agents, Arch. Int. Pharmacodyn., 136 (1962) 353-384. 195 Guzman, F., Braun, C., Lira, R.K.S., Potter, G.D. and Rodgers, D.W., Narcotic and non-narcotic analgesics wlfich block visceral pain evoked by the intraarterial injection of bradykinin and other algesic agen,,s, Arch. int. Pharmacodyn., 149 (1964) 571-588. 196 Gyires, K. and Totma, Z., The use of the writhing test in mice for screening different types of analgesia, Arch. Int. Pharmacodyn., 267 (1984) 131-140. 197 Hiibler, H.-L, A novel type of unmyelinated chemosensitire nociceptors in the acutely inflamed urinary bladder, Agents Actions, 25 (1988) 219-221. 198 Hiibler, H.-J., J~inig, W. and Koltzenberg, M., Dichotomiring unmyelinated afferents supplying pelvic viscera and perineum are rare in sacral segments of the cat, Neurosci. Lett., 94 (1988) 119-124. 199 Hancock, M.B., Foreman, R.D. and Willis, W.D., Convergence of visceral and cutaneous input onto spinothalamic tract cells in the thoracic spinal cord of the cat, Exp. Neurol., 47 (1975) 240-248. 200 Hancock, M.B., Rigamonti, D.D. and Bryan, R.N., Convergence in the lumbar spinal cord of pathways activat~,~ by splanchnic nerve and hind limb cutaneous nerve stimulation, Exp. Neurol., 38 (1973) 337-348.
225 201 Hanson, K.M., Hemodynamic effects of distension of the :log small intestine, Am. J. Physiol., 225 (1973) 456-460. 202 Hanson, K.M. and Moore, F.T., Pressure-volume relationships and bloodflow in the distended colon, Am. J. Physiol., 217 (1969) 35-39. 203 Hardy, J.D., Wolf, H.G. and Good¢ll, H., Pain Sensations and Reactions, Williams and Wilkins, Baltimore, MD, 1952. 204 Hashimoto, K., Hirose, M., Furakawa, S., Hayakawa, H. and Kimura, E., Changes in hcmodynamics and bradykinin concentrations in coronary sinus blood in experimental coronary artery occlusion, Jpn. Heart J., 18 (1977) 679689. 205 Haupt, P., J~nig, W. and K61fler, W., Response pattern of visceral afferent fibres, supplying the colon, upon chemical and mechanical stimuli, Pfliigers Arch., 398 (1983) 41-47. 206 Hazarika, N.H., Coote, J. and Downman, C.B.B., Gastrointestinal dorsal root viscerotomes in the cat, J. Neurophysiol., 27 (1964) 107-116. 207 Head, H., On disturbances of sensation, with special reference to the pain of visceral diseases, Brain, 16 (1893) 1-133. 208 Hvndershot, L.C. and Forsaith, J., Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics, J. Pharmacol. Exp. Ther., 125 (1959) 237-240. 209 Hertz, A.F., The sensibility of the alimentary tract in health and disease, Lancet, i (1911) 1051-1056; 11191124; 1187-1193. 210 Hino, O., Kanafusa, K. and Tsunekawa, K., Quantitative histological study of spinal afferent innervation on the ventral surface of the cat stomach by horseradish peroxidase (HRP) method, Experientia, 35 (1979) 379-380. 211 Hinsey, J.C. and Phillips, R.A., Observations upon diaphragmatic sensation, J. Ncurophysiol., 3 (1940) 175-181. 212 Hedge, G.B. and Messer, A.L., The electrocardiogram in biliary tract disease and during experimental biliary distension: clinical observations on 26 patients, Surg. Gynecol. Obstet., 86 (1948) 617-626. 213 Holdstock, D.J., Misiewicz, J.J. and Waller, S.L., Observations on the mechanism of abdominal pain, Gut, 10 (1969) 19-31. 214 Holt, I.L., Coulombe, P.R. and Kneupfer, M.M., Role of nucleus raphe magnus (NRM) in modulation of renal afferent input, Neurosci. Abst., 14 (1988) 174. 215 Honda, C.N., Visceral and somatic afferent convergence onto neurons near the central canal in the sacral spinal cord of the cat, J. Ncurophysiol., 53 (1985) 1059-1078. 216 Honda, C.N., Rethelyi, M. and Petrusz, P., Preferential immunohistochemical localization of vasoactive intestinal polypeptide (V!P) in the sacral spinal cord of the cat: light and electron microscopic observations, J. Neurosci., 3 (1983) 2183-2196. 217 Hornby, J.B. and Rose, J.D., Responses of caudal brain-
stem neurons to vaginal and somatosensory stimulation in the rat and evidence of genital-nociceptive interactions, Exp. Neurol., 51 (1976) 363-376. 218 Horton, E.W.. The role of bradykinin in the periFh~.ral nervous system, Ann. NY Acad. Sci., 104 0963) 250-257. 219 Hulsebosch, C.E. and Coggeshall, R.E., An analysi~ of the axe, populations in the nerves to the pelvic viscera in ',he rat, J. Comp. Neurol., 211 (1982) 1-10. 220 lwamoto, G.A., Waldrop, T.G., Longhurst, J.C. and Ordway, G.A., Localization of the cells of origin for primary afferent fibers supplying the gall bladder of the cat, Exp. Neuroi., 84 (1984) 709-714. 221 Jain, S.K., Subramanian, S., Julka, D.B. and Guz, A., Search for evidence of lung chemoreflexes in man: study of respiratory and circulatory effects of phenyldiguanide and Iobeline, Clin. Sci., 46 (1972) 163-177. 222 Jiinig, W. and Koltzenberg, M., The neural basis of consciously perceived sensations from the gut, Gut, in press. 223 J~inig, W. and McLachlan~ EM., O r d i n a t i o n of lumbar spinal outflow to distal colon and pelvic organs, Physiol. Rev., 67 (1987) 1332-1404. 224 Jiinig, W. and Morrison, J.F.B., Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 87-114. 224a Janssen, B.J.A., Van Essen, H., Struyker Boudier, H.A.J. and Smits, J.F.M., Hemodynamic effects of activation of renal and mesenteric sensory nerves in rats, Am. J. Physiol., 257 (1989) R29-R36. 225 ]avert, C.T. and Hardy, J.D., Measurement of pain intensity in labor and its physiologic, neurologic and pharmacologic implications, Am. J. Obstet. Gynecol., 60 (1950) 552-563. 226 Jeanningros, R., Modulation of lateral hypothalamus single unit activity by gastric and intestinal disten~ion, J. Auton. Nerv. Syst., !1 (1984) !-11. 227 Jensen, F.M., Madsen, J.B., Ringsted, C.V. and Christensen, A., Intestinal distension test, a method for evaluating intermittant visceral pain in the rabbit, Life Sci., 43 (1988) 747-754. 228 Iohansson, B. and Langston, J.B., Reflex influence of mesenteric afferents on renal, intestinal and muscle blood flow and on intestinal motility, Acta Physiol. Scand., 61 (1964) 400-412. 229 Jones, C~4., Pain from. the digestive tract, Prec. Ass. Res. Nerv. Ment. Dis., 23 (1943) 274-289. 230 Jones, C.M. and Pierce, F.D., Mechanism and reference of pain from the lower intestinal tract, Trans. Ass. Am. Physcns, 46 (1931) 311-312. 231 Kachelhoffer, J., Pousse, A., Marescaux, J., Iturizaga, M. and Grenier, J.F., Effects of motility and luminal distension on dog small intestine hemodynamics, Eur. Surg. Res., 10 (1978) 184-193.
226 232 Kamikawa, K., Tatsua, S., Koshino, K. and Kuru, M., Analysis of lateral column units related to vesical reflexes, Exp. Neurol., 6 (1962) 271-284. 233 Kanui, T.I., Responses of spinal cord neurones to noxious and non-noxious stimulation of the skin and testicle of the rat, Neurosci. Lett., 58 (1985) 315-319. 234 Katz, L.N., Mayne, W. and Weinstein, W., Cardiac pain presence of pain fibers in the nerve plexus surrounding the coronary vessels, Arch. Intern. Med., 55 (1935) 760-772. 235 Kawatani, M., Nagel, J. and DeGroat, W.C., Identification of neuropeptides in pelvic and pudendal nerve afferent pathways to the sacral spinal cord of the cat, J. Comp. Neurol., 249 (1986) 117-132. 236 Kend~,Jl, G.P.N., Visceral pain, Br. J. Surg., 72 (1985) 4-5. 237 Khayutin, V.M., B~az, L.A., L u ~ h k o v a , E.V., Sonina, R.S. and Chernilovs::ay~, P.E.. Chemosensitive spinal afferents: thresholds of specific and nociceptive reflexes as compared with thresholds of excitation for receptors and axons. In: A. Iggo and O.B. llyinski (Eds.), Somatosensory and Visceral Receptor Mechanisms. Prog. Brain Res., Vol. 43, Elsevier, Amsterdam, 1974, pp. 293-306. 238 Kimura, E., Hashimoto, K., Furukawa, S. and Hayakawa, H., Changes in bradykinin level in coronary sinus blood after the experimental occlusion of a coronary artery, Am. Heart J., 85 (1973) 635-647. 239 King, B.F. and Szurszewski, J.H., Mechanoreceptor pathways from the distal colon to the autonomic nervous system in the guinea pig, J. Physiol. (Lond.), 350 (1984) 93-107. 240 Kingham, J.C.G. and Dawson, A.M., Origin of chronic right upper quadrant pain, Gut, 26 (1985) 783-788. 241 Kinsella, V.J., Sensibility in the abdomen, Br. J. Surg., 27 (1940) 449-463. 242 Klein, C.M. and Burden, H.W., Anatomical localization of afferent and postganglionic sympathetic neurons innervating the rat ovary, Neurosci. Lett., 85 (1988) 217-222. 243 Knuepfer, M.M. and Schramm, L.P., Properties of re. nobulbar afferent fibers in rats, Am. J. Physiol., 248 (1985) Rl13-Rl19. 244 Knuepfer, M.M. and Schramm, L.P., The conduction velocities and spinal projections of single renal afferent fibers in the rat, Brain Res., 435 (1987) 167-173. 245 Knuepfer, M.M., Akeyson, E.W. and Schramm, L.P., Spinal projections of renal afferent nerves in the rat, Brain Res., 446 (1988) 17-25. 246 Koltzenburg, M. and McMahon, S.B., Plasma extravasation in the rat urinary bladder following mechanical, electrical and chemical stimuli: evidence for a new population of chemosensitive primary sensory afferents, Neurosci. Lett., 72 (1936) 352-356. 247 Komisaruk, B.R. and Whipple, B., Vaginal stimulationproduced analgesia in rats and ,vomen, Ann. NY A~ad. Sci., 467 (1986) 30-39. 248 Kostreva, D.R., Hopp, F.A. and Kampine, ~ ~., Depressor responses to stimulation of sympathetic afferents in monkeys and dogs, Am. J. Physiol., 240 (1981) R23-R28.
249 Kostreva, D.R., Seagard, J.L., Castaner, A. and Kampine, J.P., Reflex effects of renal afferents on the heart and kidney, Am. J. Physiol., 241 (1981) R286-R292. 250 Kow, L.-M., Zemlan, F.P. and Pfaff, D.W., Responses of lumbosacral spinal units to mechanical stimuli rc!ated to analysis of lordosis reflex in female rats, J. Neurophysiol., 43 (1980) 27-45. 251 Kramer, P. and Hollander, W., Comparison of experimental esophageal pain with clinical pain of angina pectoris and esophageal disease, Gastroenterology, 29 (1955) 719743. 252 Kuilmann, R., Cardiovascular reflexes controlling regional sympathetic outflow during coronary artery occlusion, Basic Res. Cardiol., 77 (1982) 507-519. 253 Kumazawa, T., Sensory innervation of reproductive organs. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 115-132. 254 Kuo, D.C. and DeGroat, W.C., Primary afferent projections of the major splanchnic nerve to the spinal cord and gracile m ~leus of the cat, J. Comp. Neurol., 231 (1985) 421-434. 255 Kuo, D.C., Nadelhaft, I., Hisamitsu, T. and DeGroat, W.C., Segmental distribw: and central projections of renal afferent fibers in : cat studied b,, " :~anglionic transport of horseradish peroxidase, J. Comp. Neurol., 216 (1983) 162-174. 256 Kuo, D.C., Oravitz, J.J. and DeGroat, W.C., Tracing of afferent and efferent pathways in the left inferior cardiac nerve of the cat using retrograde and transganglionic transport of horseradish peroxidase, Brain Res., 321 (1984) 111-118. 257 Labate, J.S. and Reynolds, S.R.M., Sensory pathways of the ovarian plexus: an experimental study, Am. J. Obstet. Gynecol., 34 (1937) 1-11. 258 Langley, J.N., The autonomic nervous system, Brain, 26 (1903) 1-26. 259 Lankisch, P.G., Acute and chronic pancreatitis: an update on management, Drugs, 28 (1984) 554-564. 260 Lappe, R.W., Webb, R.L. and Brody, M.J., Selective destruction of renal afferent versus efferent nerves in rats, Am. J. Physiol., 249 (1985) R634-R637. 261 Laskey, W., Schondorf, R. and Polosa, C., Intersegraental connections and interactions of myelinated somatic and visceral afferents with sympathetic preganglionic neurons in the unanesthetized spinal cat, J. Auton. Nerv. $yst., 1 (1979) 69- 76. 262 Lasser, R.B., Bond, J.H. and Levitt, M.D., The role of intestinal gas in functional abdominal pain, New Engl. J. Med., 293 (1975) 524-526. 263 Latimer, P., Campbell, D., Latimer, M., Sarna, S., Daniel, E. and Waterfall, W., Irritable bowel syndrome: a test of the colonic hyperalgesia hypothesis, J. Behav. Med., 2 (1979) 285-295. 264 Laurenberg, S. and Srensen, K.E., Cervical dorsal root ganglion cells with collaterals to both shoulder skin and
227
265
266
267
268 269
270
271 272 273 274
275
276
277 278
279
280
281
the diaphragm. A fluorescent doub|c-tabelling stt~3y i~ the rat. A model for referred pain.'?, Brain Res., 331 (1985) 160-163. Lautt, W.W., Hepatic nerves: a review of their functions and effects, Can. J. Physiol. Pharmacol., 58 (1980) 105123. Layne, J.A. and Bergh, G.S., An experimental study of pain in the human biliary tract induced by spasm of the sphincter of Oddi, Surg. Gynecol. Obstet., 70 (1940) 18-24. Learmonth, J.R., Neurosurgery in the treatment of diseases of the urinary bladder. II. Treatment of vesical pain, J. Urol., 26 (1931) 13-24. Leek, B.F., Abdominal and pelvic visceral receptors, Br. Med, Bull., 33 (1977) 163-168. Lembeck, F. and Skofitsch, G., Visceral pain reflex after pretreatment with capsaicin and morphine, NaunynSchmiedeberg's Arch. Pharmacol., 321 (1982) 116-122. Lew, W.Y.W. and Longhurst, J.C., Substance P, 5-hydroxytryptamine, and bradykinin stimulate abdominal visceral afferents, Am. J. Physiol., 250 (1986) 465-473. Lewis, H.P., Pain in acute and chronic diseases of the liver, Ann. Intern. Med., 35 (1951) 878-888. Lewis, M.I., Reversible ischemic colitis, Dis. Colon Rectum, 16 (1973) 121-126. Lewis, T., Pain, McMillan, London, 1942. Lewis, T. and Kellgren, J.H., Observations related to referred pain, viscerosomatic reflexes and other associated phenomena, Clin. Sci., 4 (1939) 47-71. Lira, R.K.S., Guzman, F., Rodgers, D.W., Gore, K., Braun, C., Dickerson, G.D. and Engle, RJ., Site of action of narcotic and non-narcotic analgesics determined by blocking bradykinin-evoked visceral pain, Arch. Int. Pharmacodyn., 152 (1964) 25-58. Lira, R.K.S., Miller, D.G., Guzman, F., Rodgers, D.W., Rogers, R.W., Wang, S.K., Chao, P.Y. and Shih, T.Y., Pain and analgesia evaluated by the intraperitoneal bradykinin-evoked pain method in man, Ciin. Pharmacol. Ther., 8 (1967) 521-542. Lindgren, I. and Oiivecrona, H., Surgical treatment of angina pectoris, J. Neurosurg., 4 (1947) 19-39. Lipkin, M. and Sleisenger, M.H., Studies of visceral pain: measurements of stimulus intensity and duration associated with the onset of pain in esophagus, ileum and colon, J. Clin. Invest., 37 (1957) 28-34. Littler, W.A., Honour, A.J., Slaight, P. and Stott, F.D., Direct arterial pressure and electrocardiogram in unrestricted patients with angina pectoris, Circulation, 48 (1973) 125-130. Lombardi, F., Bella, P.D., Casati, R. and Malliani, A., Effects of intracoronary administration of bradykinin on the impulse activity of afferent sympathetic unmyelinated fibers with left ventricular endings in the cat, Circ. Res., 48 (1981) 69-75. Longhurst, J.C., Ashton, J.H. and lwamoto, G.A., Cardiovascular reflexes resulting from caps-~cin-stimulated gastric receptors in anesthetized dogs, Circ. Res., 46 (1980) 780-788.
282 Longhurst, J.C. and Dittman, L.E., Hypoxia, bradykinin, and prostaglandins stimulate ischemically sensitive visceral afferents, Am. J. Physiol., 253 (1987) H556-H567. 283 Longhurst, J.C. and Ibarra, J., Sympathoadrenal mechanisms in hemodynamic responses to gastric distension in cats, Am. J. Physiol., 243 (1982) 748-753. 284 Longhurst, J.C., Spilker, H.L. and Ordway, G.A., Cardiovascular re qexes elicited by passive gastric distension in anesthetized cats, Am. J. Physiol., 240 (1981) 539-545. 285 Longhurst, J.C., Stebbins, C.L. and Ordway, G.A., Chemically induced cardiovascular reflexes arising from the stomach of the cat, Am. J. Physiol., 247 (1984) H459H466. 286 MacKenzie, J., Some points bearing on the association of sensory disorders and visceral disease, Brain, 16 (1893) 321-353. 287 MacKenzie, J., Symptoms and their Interpretation, Shaw, London, 1909. 288 MacKenzie-Taylor, D.R., Saatio, K. Heath, G.F. and Rech, R.H., Comparison in rats of mu and kappa opioids on pain of somatic and visceral origin, Physiologist, 28 (1986) 96. 289 Magni, F. and Carobi, C., The afferent and preganglionic parasympathetic innervation of the rat liver, demonstrated by t~e retrograde transport of horseradish peroxidase, J. Auton. Nerv. Syst., 8 (1983) 237-260. 290 Malliani, A., Cardiovascular sympathetic afferent fibers, Rev. Physiol. Biochem. Pharmacol., 94 (1982) 11-70. 291 Malliani, A., The link between transient myocardial ischemia and pain. In: B.S. Singh (Ed.), Silent Myocardial Ischemia and Angina, Pergamon Press, New York, 1988, pp. 34-47. 292 Malliani, A. and Lombardi, F., Consideration of the fundamental mechanisms eliciting cardiac pain, Am. Heart J., 103 (1982) 575-578. 293 Malliani, A., Pagani, '.~.. and Bergamaschi, M., Positive feedback ~ymp~thefic :cflex~ and hypertension, Am. J. Cardiol., 44 (1979) 860-865. 294 Malliani, A., Pagani, M., Pizziaelli, P., Furlan, R. and Guzzetti, S., Cardiovascular reflexes mediated by sympathetic afferent fibers, J. Auton. Nerv. Syst., 7 (1983) 295-301. 295 Malliani, A., Recordati, G. and Schwartz, P.J., Nervous activity of afferent cardiac sympathetic fibres with atrial and ventricular endings, J. Physiol. (Lend.), 229 (1973) 457-469. 296 Malliani, A., Schwartz, P.J. and Zanchetti, A., A sympathetic reflex elicited by experimental coronary artery occlusion, Am. J. Physiol.~ 217 (1969) 703-709. 297 Martin, S.E., Pilkington, D.M. and Longhurst, J.C., Coronary vascular responses to chemical stimuli of abdominal visceral organs, Am. J. Physiol., 256 (1989) H735-H744. 298 Martin, S.J. and Gordham, L.W., Cardiac pain: an experimental study with reference to the tension factor, Arch. Intern. Med., 62 (1938) 840-852.
228 299 McArthur, S.W. and Wakefield, H., Observations on the human electrocardiogram during experimental distension of the gall bladder, J. Lab. Clin. Med., 30 (1945) 349-351. 300 McGowan, J.M., Butsch, W.L. and Waiters, W., Pressure in the common bile duct of man: its relation to pain following cholecystectomy, JAMA, 106 (1936) 2227-2230. 301 McLachlan, E.M., The components of the hypogastric nerve in male and female guinea pigs, J. Auton. Nerv. Syst., 13 (1985) 327-342. 302 McLaughlin, Jr., C.W. and Levering, J.W., The effects of increased intragastric pressure upon thoracic and abdominal a~terial and venous pressures, Surg. Gynecol. Obstet., 58 (1934) 699-704. 303 McLeod, J.G., The representation of the splanchnic afferent pathways in the thalamus of the cat, J. Physiol. (Lond.), 140 (1958) 462-478. 304 McMahon, S.B., Sensory-motor integration in urinary bladder function. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. B~ein i.~es., Vol. 67, Elsevier, Amsterdam, 1986, pp. 245-254. 305 McMahon, S.B., Neuronal arid beh~,viorai consequences of chemical inflammation of rat urinary bladder, Agents Actions, 25 (1988) 231-233. 306 McMahon, S.B. and Abel, C., A model for the study of visceral pain states: chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals, Pain, 28 (1987) 109-127. 307 McMahon, S.B. and Morrison, J.F.B., Two groups of spinal interneurones that respond to stimulation of the abdominal viscera of the cat, J. Physiol. (Lond.), 322 (1982) 21-34. 308 McMahon, S.B. and Morrison, J.F.B., Spinal neurones with long projections activated from the abdominal viscera of the cat, J. Physiol. (Lond.), 322 (1982) 1-20. 309 McNeill, D.L. and Burden, H.W., Convergence of sensory processes from the heart and left ulnar nerve onto a single afferent perikaryon: a neuroanatomical study in the rat employing fluorescent tracers, Anat. Rec., 214 (1986) 441444. 310 McSwiney, B.A. and Suffolk, S.F., Segmental distribution of certain visceral afferent neurones of the pupillo-dilator reflex in the cat, J. Physiol. (Lond.), 93 (1938) 104-116. 3!! Meckler, R.L. and Weaver, L.C., Characteristics of ongoing and reflex discharge of single splenic and renal sympathetic postganglionic fibres in cats, J. Physiol. (Lond.), 396 (1988) 139-153. 312 Mei, N., Sensory structures in the viscera, Prog. Sens. Physiol., 4 (1983) 1-42. 313 Mei, N., Intestinal chemosensmvity, Physiol. Key., 65 (1985) 211-237. 314 Mellanby, J. and Pratt, C.L.G., The reactions of the urinary bladder of the cat under conditions of constant volume, Proc. Roy. Soc. Lond. B, 128 (1940) 186-29i. 315 Mense, S. and Prabhakar, N.R., Spinal termination of nociceptive afferent fibres from deep tissue hi the ca:, Neurosci. Lett., 66 (1986) 169-174.
316 Miller, F.R., Viscero-motor reflexes, II, Am. J. Physiol., 71 (1924) 84-89. 317 Miller, F.R. and Simpson, H.M., Viscero-motor reflexes, Am. J. Physiol., 72 (1925) 231-232. 318 Miller, F.R. and Waud, R.A., Viscero-motor reflexes, IV, Am. J. Physiol., 73 (1925) 329-340. 319 Milne, R.J., Foreman, R.D., Giesler, Jr., G.J. and Willis, W.D., Convergence of cutaneous and pelvic visceral nociceptive inputs onto primate spinothalamic neurons, Pain, 11 (1981) 163-183. 320 Mizumura, K., Tadaki, E. and Kumazawa, T., Respiratory changes induced by activation of testicular afferents in dogs, Pfliigers Arch., 411 (1988) 27-33. 321 Molander, C., Ygge, J. and Dalsgaard, C.-J., Substance P-, somatostatin- and calcitonin gone-related peptide-like immunoreactivity and fluoride resistant acid phosphatase-activity in relation to retrogradely labeled cutaneous, muscular and visceral primary sensory neurons in the rat, New rosci. Lett., 74 (1987) 37-42. 322 Moore, R.M., Some experimental observations relating to visceral pain, Surgery, 3 (1938) 534-555. 323 Moore, R.M. and Singleton, Jr., A.O., A pseudoaffective reflex evoked by injections into the left coronary artery end the peripheral paths of the pain fibers which are cep~cerned, Am. J. Physiol., 113 (1935) 99-100. 324 Morgan, C., Nadelhaft, I. and DeGroat, W.C., The distribution of visceral primary afferents from the pelvic nerve to Lissauer's tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus, J. Comp. Ncuro!., 201 (1981)415-440. 325 Morgan, C., Nadelhaft, I. and DeGroat, W.C., The distribution within the spinal cord of visceral primary afferent axons carried by the lumbar colonic nerve of the cat, Brain Res,, 398 (1Q86) 11-17. 326 Morgan, C., DeGroat, W.C. and Nadeihaft, I., The spinal distribution of sympathetic preganglionic and visceral primary afferent neurons that send axons into the hypogastric nerves of the cat, J. Comp. Neurol., 243 (1986) 23-40. 327 Moriarty, K. and Dawson, A.M., Functional abdominal pain: further evidence that whole gut is affected, Br. Med. J., 284 (1982) 1670-1672. 328 Morley, J., The significance of the afferent impulses from the skin in the mechanism of abdominal pain, Lancet, ii (1929) 1240-1244. 329 Morrison, J.F.B., Splanchnic slowly adapting mechanoreceptors with punctate receptive fields in the mesentery and gastrointestinal tract of the cat, J. Physiol. (Lond.), 233 (1973) 349-361. 330 Morrison, J.F.B., The afferent innervation of the gastrointestinal tract. In: F.P. Brooks and P.W. Evers (Eds.), Nerves and the Gut, Slack, Thorofare, N J, 1977, pp. 297-322. 331 Morrison, J.F.B. and McMahon, S.B., Colonic afferents and their reflexes, Motil. Dig. Tract, 145 (1982) 19-29. 332 Morrison, L.M. and Swalm, W.A., Role of the gastroin-
229 testinal tract in production of cardiac symptoms: experimental and clinical observations, JAMA, 114 (1940) 217223. 333 Mukherjee, S.R., Effect of bladder distension on arterial blood pressure and renal circulation, J. Physiol. (Lond.), 138 (1957) 300-325. 334 Nadelhaft, I. and Booth, A.M., The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: a horseradish peroxidase study, J. Comp. Neurol., 226 (1984) 238-245. 335 Nadelhaft, 1., Roppolo, J., Morgar. C. and DeG~'oat, W.C., Parasympathetic preganglionic aeurons and visceral primary afferents in monkey sacral spinal cord revealed following application of horseradish peroxidase to pelvic nerve, J. Comp. Neurol., 216 (1983) 36-52. 336 Nance, D.M., Burns, J., Klein, C.M. and Burden, H.W., Afferent fibers in the reproductive system and pelvic viscera of female rats: anterograde tracing and immunocytochemical studies, Brain Res. Bull., 21 (1988) 701-709. 337 Nathan, P.W., Sensations associated with micturition, Br. J. Urol., 28 (1956) 126-131. 338 Nathan, P.W. and Smith, M.C., The centripetal pathway from the bladder and urethra within the spinal cord, J. Neurol. Neurosurg. Psychiat., 14 (1951) 262-280. 339 Nerdrum, T., Baker, D.G., Coleridge, H.M. and Coleridge, J.C.G., Interaction of bradykinin and prostaglandin E1 on cardiac pressor reflex and sympathetic afferents, Am. J. Physiol., 250 (1986) R815-R822. 340 Ness, T.J. and Gebhart, G.F., Characterization of neuronal responses to noxious visceral and somatic stimuli in the medial lumbosacral spinal cord of the rat, J. Neurophysiol., 57 (1987) 1867-1892. 341 Ness, T.J. and Gebhart, G.F., Quantitative comparison of inhibition of visceral and cutaneous spinal nociceptive transmission fi-o,,r the midbrain and medulla in the rat, J. Neurophysio]., 58 (1987) 850-865. 342 Ness, T.J. and Gebhart, G.F., Coloreetal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat, Brain Res., 450 (1988) 153-169. 343 Ness, T.J. and Gebhart, G.F., Characterization of neurons responsive to noxious coloreetal distension in the TI3-L2 spinal cord of the rat, J. Neurophysiol., 60 (1988) 14191438. 344 Ness, T.J. and Gebhart, G.F., Counterinitation: inhibition of visceral and cutaneous nociception, Neurosci. Abst., 14 (1988) 710. 345 Ness, T.J. and Gebhart, G.F., Characterization of superficial T13-L2 dorsal horn neurons encoding for eolorectal distension in the rat: comparison with neurons in deep laminae, Brain Res., 486 (1989) 301-309. 346 Ness, T.J. and Gebhart, G.F., Differential effects of morphine and clonidine upon visceral and cutaneous nociceptive transmission in the rat, J. Neurophysiol., 62 (1989) 220-230. 346a Ness, T.J. and Gebhart, G.F., Inflammation potentiates
responses to colorectal distension in the rat, Neurosci. Abst., 15 (1989) 847. 347 Neuhuber, W., The central projections of visceral primary aff,~re',t neurons of the inferior mesenteric plexus and hypogastric nerve and the location of the related sensory and preganglionic sympathetic cell bodies in the rat, Anat. Embryol., 164 (1982) 413-425. 348 Neuhuber, W.L. and Niederle, B., Spinal ganglion cells innervating the stomach of the rat as demonstrated by somatopetal transport of horseradish peroxidase, Anat. Embryol., 155 (1979) 355-362. 349 Neuhuber, W.L., Sandoz, P.A. and Fryscak, T., The central projections of primary afferent neurons of greater splanc.hnic and intercostal nerves in the rat, Anat. Embryol., 174 (1986) 123-144. 350 Newman, H.F. and Northrup, J.D., Intraluminal pressure and electrical excitability of the human gall bladder, J. Appl. Physiol., 9 (1956) 121-129. 351 Newman, P.P., Changes in arterial blood pressure following stimulation of the gall bladder, J. Physiol. (Lond.), 119 (1953) 46P-47P. 352 Newman, P.P., Interaction in the visceral sensory areas of the cerebral cortex, J. Physiol. (Loud.), 157 (1961) 29P. 353 Newman, P.P., The representation of some visceral afferents in the anterior lobe of cerebellum, J. Physiol. (Loud.), 182 (1966) 195-208. 354 Newman, P.P. and Paul, D.H., The effects of stimulating cutaneous and splanchnic afferents on cerebellar unit discharges, J. Physiol. (Lond.), 187 (1966) 575-582. 355 Newman, P.P. and Paul, D.H., The projection of splanchnic afferents on the cerebellum of the cat, J. Physiol. (Lond.), 202 (1969) 223-237. 356 Nolan, P.N., Luk, D.E. and Staszewska-Barczak, J., Reflex effects evoked from the parietal pericardium in the dog: comparison with responses from the visceral pericardium, Basic Res. Cardiol., 78 (1983) 654-664. 357 Northover, B.J., The permeability of plasma .nroteins of the peritoneal blood vessels of the mouse, and the effect of substances that alter permeability, J. Patrol. Baeteriol., 85 (1963) 361-370. 358 Ockerblad, N.F. and Carlson, H.E., The distribution of ureterai pain, J. Urol., 39 (1938) 745-750. 359 Ogilvie, W.H., Some notes on the surgical aspects of gall-stone disease, Guy's Hosp. Rep., 75 (1925) 78-97~ 360 Ohman, U., Studies on small intestinal obstruction, Acta Chir. Stand., 141 (1975) 536-549. 361 Oldfield, B.J. and McLachlan, E.M., Localization of sensory neurons traversing the stellate ganglion of the cat, J. Comp. Neurol., 182 (1978) 915-922. 362 Ordway, G.A. and Longhurst, J.C., Cardiovascular reflexes arising from the gallbladder of the cat: effects of capsaicin, bradykinin, and distension, Circ. Res., 52 (1983) 26-35. 363 Ordway, G.A., Boheler, K.R. and Longhurst, J.C., Stimulating intestinal afferents reflexly activates cardiovascular system in cats, Am. J. Physiol., 254 (1988) H354-H360. 364 Ordway, G.A., Longhurst, J.C. and Mitchell, J.H., Stimu-
230
365
366
367
368 369
370
371
372
373 374
375
376
377
378
379
380
lation of pancreatic afferents reflexly activates the cardiovascular system in cats, Am. J. Physiol., 245 (1983) R820-R826. Pagani, N., Pizzinelli, P., Bergamaschi, M. and Malliani, A., A positive feedback sympathetic pressor reflex during the stretch of the thoracic aorta in conscious dogs, Circ. Res., 50 (1982) 125-132. Pagani, M., Pizzinelli, P., Furlan, R., Guzzetti, S., Rimoldi, O., Sandrone, G. and Malliani, A., Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs, Circ. Res., 56 (1985) 175-183. Pahlin, P.E. and Kewenter, J., Reflexogenic contraction of the ileo-cecal sphincter in the cat following small or large intestinal distension, Acta Physiol. Stand., 95 (1975) 126132. Paintal, A.S., Thoracic receptors connected with sensation, Br. Med. Bull., 33 (1977) 169-174. Paintal, A.S., The visceral sensations - some basic mechanisms. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. in Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 3-19. Patei, K.P. and Knuepfer, M.M., Effect of afferent renal nerve stimulation on blood pressure, heart rate and noradrenergic activity in conscious rats, J. Auton. Nerv. Syst., 17 (1986) 121-130. Pavlasek, J., Gokin, A.P. and Duda, P., Visceral pain: responses of the reticular formation neurons to gallbladder distension, J. Physiol. (Paris), 73 (1977) 335-346. Pavlasek, R. and Duda, P., The relation of activity of postsynaptic elements in the spinal cord to propriospinal and spino-bulbo-spinal reflexes, Physiol. Bohemoslov., 20 (1971) 398. Payne, W.W. and Poulton, E.P., Visceral pain in the upper alimentary tract, Quart. J. Med., 17 (1923) 53-80. Payne, W.W. and Poulton, E.P., Experiments on visceral seasation. 1. The relation ot pain to activity in the human esophagus, J. Physiol. (Lond.), 63 (1927) 217-241. Payne, W.W. and Poulton, E.P., Experiments on visceral sensation. II. The 'nausea' and 'sinking': oesophageal reeiexes and counter-irritation, J. Physiol. (Lond.), 65 (1928) 157-172. Pearcy, J.F., Priest, W.S. and Van Allen, C.M., Pain due to temporary occlusion of the coronary arteries in dogs, Am. Heart J., 4 (1929) 390-391. Penfield, W., The neurological mechanisms of angina pec-. toris and i:s relation to surgical therapy, Am. J. Med. Sci., 170 (1925) 864-873. Pert'in, J. et Crousillat, J., Effets de la stimulation des mgcanorgcepteurs splanchniques sur ractivit6 des cellules c6r6belleuses de Purkinje, Exp. Brain Res., 37 (1979) 405416. Perrin, J. and Crousillat, J., Responses of single units in the inferior olive nucleus *.o stimulation of the splanchnic afferents in the cat, J. Auton. Nerv. Syst., 2 (1980) 15-22. Perrin, J. and Crousillat, J., Splanchnic afferent input to the lateral reticular nucleus of the cat, J. Auton. Nerv. Syst., 8 (1983) 383-393.
381 Peterson, D.F. and Brown, A.M., Pressor reflexes produced by stimulation of afferent fibers in the cardiac sympathetic nerves of the cat, Circ. Res., 28 (1971) 605610. 382 Peterson, D.F. and Brown, A.M., Functional afferent innervation of testis, J. Neurophysiol., 36 (1973) 425-433. 383 Pierau, F.K., Fellmer, G. and Taylor, D.C.M., Somatovisceral convergence in cat dorsal root ganglion neurones demonstrated by double-labelling with fluorescent tracers, Brain Res., 321 (1984) 63-70. 384 Polland, W.S. and Bloomfield, A.L., Experimental referred pain from the gastrointestinal tract. I. The esophagus, J. Clin. Invest., 10 (1931) 435-452. 385 Pomeranz, B., Wall, P.D. and Weber, W.V., Cord cells responding to fine myelinated afferents from viscera, muscle and skin, J. Physiol. (Lond.), 199 (1968) 511-532. 386 Poole, J.W., Sammartano, R.J. and Boley, S.J., Hemodynamic basis of the pain of chronic mesenteric ischemia, Ann. Intern. Med., 153 (19~7) 171-180. 387 Pozo, F., Fueyo, A., Esteban, M.M. and Rojo-Ortega, J.M., Blood pressure changes after gastric mechanical and electrical stimulation in rats, Am. J. Physiol., 249 (1985) 739-744. 388 Prabhakar, N.R., Marek, W. and Loeschke, H.H., Altered breathing pattern elicited by stimulation of abdominal visceral afferems, J. Appl. Physiol., 58 (1985) 1755-1760. 389 Price, D.D., Bushnell, M.C. and ladarola, M.J., Primary afferent and sacral dorsal horn neuron responses to vaginal probing in the cat, Neurosci. Lett., 26 (1981) 67-72. 390 Ravidin, I.S., Royster, H.P. and ~/anders, G.B., Reflexes originating in the common duct giving rise to pain simulating angina pcctoris, Ann. Surg., 115 (1942) 1055-1065. 391 Ray, B.S. and Neill, C.L., Abdominal visceral sensation in man, Ann. Surg., 126 (1947) 709-724. 392 Reading, A.E., The internal structure of the McGill Patt~ Questionnaire in dysmenorrhea patients, Pain, 7 (1979) 353-358. 393 Reeve, E.B., Nanson, E.M. and Rundle, F.F., Observations on inhibitory respiratory reflexes during abdominal surgery, Clin. Sci., 10 (1951) 65-87. 394 Reimann, K.A. and Weaver, L.C., Contrasting reflexes evoked by chemical activation of cardiac afferent nerves, Am. J. Physiol., 239 (1980) H316-H325. 395 Richter, J.E., Barish, C.F. and Castell, D.O., Abnormal sensory perception in patients with esophageal chest pain, Gastroenterology, 91 (1986) 845-852. 396 Risholm, L., Studies on renal colic and its treatment by posterior splanchnic block, Acta Chir. Scand. Suppl., 184 (1954) 1-64. 397 Ritchie, J., Pain from distension of the pelvic colon by infating a balloon in the irritable colon syndrome, Gut, 14 (1973) 125-132. 398 Ritchie, J., Pain in IBS, Pract. Gastroenterol., 3 (1979) 16-23. 399 Ritchie, J., Mechanisms of pain in the irritable bowel syndrome. In: N. Read (Ed.), Irritable Bowel Syndrome, Grune and Stratton, New York, 1985, pp. 163-171. 400 Re~ato, E.F., Chu, W.H., MuUen, J.L. and Rosato, F.E.,
231
401
402
403 404
405 406
407
408
409
410
411
412
413
414
415
416 417
418
Peritoneal lavage treatment of experimental pancreatitis, J. Surg. Res., 12 (1972) 138-140. Rose, J.D., Response properties and anatomical organization of pontine and medullary units responsive to vaginal stimulation in the cat, Brain Res., 97 (1975) 79-93. Rose, J.D., Responses of midbrain neurons to genital and somatosensory stimulation in estrous and anestrous cats, Exp. Neurol., 49 (1975) 639-652. Ross, J., On the segmental distribution of sensory disorders, Brain, 10 (1888) 333-361. Roughgarden, J.W., Circulatory changes associated with spontaneous angina pectoris, Am. J. Med., 41 (1966) 9.~7961. Routledge, J.H. and Elliot, H., Pain studies in pelvic viscera, Am. J. Obstet. Gynecol., 83 (1962) 701-709. Rubia, F.J., The projection of visceral afferents to the cerebellar cortex of the cat, Pfliigers Arch., 320 (1970) 97-110. Rubia, F.J. and Phelps, J.B., Responses of the cerebellar cortex to cutaneous and visceral afferents, Pfliigers Arch., 314 (1970) 68-95. Ruch, T.C., Pathophysiology of pain. In: T.C. Ruch, J.D. Patton, J.W. Woodbury and A.L. Lowe (Eds.), Neurophysiology, Saunders, Philadelphia, PA, 1961, pp. 350-368. Rucker, H.K. and HoUoway, J.A., Viscerosomatic convergence onto spinothalamic tract neurons in the cat, Brain Res., 243 (1982) 155-157. Ruge, D. and Wetzel, N., The surgical relief of intractable abdominal pain, Surg. Clin. N. Am., 34 (1954) 269-275. Riihle, W., Dembowsky, K., Czachurski, J. and Seller, H., Segmental distribution of afferent fibers in the left inferior cardiac nerve of the cat studied by anterograde transport of horseradish peroxidase, Neurosci. Lett., 56 (1985) 353358. Ryall, R.W. and Piercey, M.F., Visceral afferent and efferent fibers in sacral ventral roots in cats, Brain Res., 23 (1970) 57-65. Rybicki, D.J., Longhurst, I.C. and Kaufman, M.P., Stimulation of splanchnic afferents reflexly relaxes tracheal smooth muscle in dogs, Am. J. Physiol., 55 (1983) 427-432. Sarnoff, S.J. and Yamada, S.I., Evidence from reflex control of arterial pressure from abdominal receptors with special reference to the pancreas, Circ. Res., 7 (1959) 325-335. Satpathy, N.K. and AI-Sattar, N.A., The effects of acute oesophageal distension on arterial blood pressure, E.C.G. and respiration in the dog, Indian J. Physiol. Pharmacol., 28 (1984) 105-114. Sawchenko, P.E. and Friedman, M.I., Sensory functions of the liver - a review, Am. J. Physiol., 236 (1979) RS-R20. Schmauss, C., Shimohigashi, Y., Jensen, T.S., Rodbard, D. and Yaksh, T.L., Studies on spinal opiate receptor pharmacology. III. Analgetic effects of enkephalin dimers as measured by cutaneous-thermal and visceral-chemical evoked responses, Brain Res., 337 (1985) 239-215. Schondorf, R. and Polosa, C.~ Effects of urinary bladder afferents on respiration, J. Appl. Physiol., 48 (1980) 826832.
419 Scho:,dorf, R., Laskey, W. and Polosa, C., Upper thoracic sympathetic neuron responses to input from urinary afferents, Am. J. Physiol., 245 (1983) R311-R320. 420 Schi'ager, V.L. and Ivy, A.C., Symptoms produced by distension of the gallbladder and biliary tracts: a clinical and experimental study, Surg., Gynecol. Obstet., 47 (1928) 1-13. 421 ¢" ' ,.,c~zer, M. and Spencer, W.A., Convergence of visceral and cutaneous afferent pathways in the lumbar spinal cord, Brain Res., 14 (1969) 331-348. 422 Selzer, M. and Spencer, W.A., Interactions between visceral and cutaneous afferents in the spinal cord: reciprocal primary afferent fiber depolarization, Brain Res., 14 (1969) 349-366. 47~t Se.~sle, B.J., t ]u, J.W., Amano, N. and Zhong, ~.~.,Convergence of cut~.neous, tooth pulp, visceral, neck and muscle afferents onto nociceptive and non-nociceptive neurones in trigeminal subnucleus c,~udalis (medullary dorsal horn) and its implications for referred pain, Pain, 27 (1986) 219-235. 424 Sharkey, K.A., Sobrino, J.A. and Cervero, F., Evidence for a visceral afferent origin of substance P-like immunoreactivity in lamina V of the rat thoracic spinal cord, Neuroscience, 22 (1987) 1077-1083. 425 Sherrington, C.S., The Integrative Action of the Nervous System, Yale Univ. Press, New Haven, CT, 1906. 426 Shukla, M., Dey, P.K. and Tripathi, S.N., Effect of graded distension of urinary bladder on arterial blood pressure and neurohumors in rabbits, Indian J. Physiol. Pharmacol., 29 (1985) 159-164. 427 Sicuteri, F., FanciuUacci, M. and Anselmi, B., Bradykinin release and inactivation in man, Int. Arch. Allergy, 22 (1963) 77-84. 428 Silen, W., Cope's Early Diagnosis of the Acute Abdomen, 16th edn., Oxford Univ. Press, New York, 1983. 429 Simon, O.R. and Schramm, L.P., The spinal course and medullary termination of myelinated renal afferents in the rat, Brain Res., 290 (1984) 239-247. 430 Sinclair, D.C., Weddeli, G. and Feindel, W.H., Referred pain and associated phenomena, Brain, 71 (1948) 184-211. 431 Skoglund, R.W., McRoberts, J.W. and Ragde, H., Torsion of the s,pe:.rmatic cord: a review of the literature and an analysis of 70 new cases, J. Urol., 104 (1970) 604-607. 432 Smits, J.F.M. and Brody, M.J., Activation of afferent renal nerves by intrarenal l,radykinin in conscious rats, Am. J. Physiol., 247 (1984) 1003-1008. 433 Sonoda, H., Ikenoue, K. and Yokota, T., Periaqueductal gray inhibition of viscerointercostal and galvanic skin reflexes, Brain Res., 369 (1986) 91-102. 434 Staniland, J.R., Ditchburn, J. and DeDombal, F.T., Clinical presentation of acute abdomen: study of 600 patients, Br. Med. J., 3 (1972) 393-398. 435 Staszewska-Barczak, J. and Dusting, G.J., Sympathetic cardiovascular reflex initiated by bradykinin-induced stimulation of cardiac pain receptors in the dog, Clin. Exp. Pharmacol. Physiol., 4 (1977) 443-452. 436 Staszewska-Barczak, J., Ferreira, S.H. and Vane, J.R., An excitatory nociceptive cardiac reflex elicited by bradykinin
232 and potentiated by prostaglandins and myocardial ischemia, Circ. Res., 10 (1976) 314-327. 437 Staszewska-Wooley, J., Luk, D.E. and Nolan, P.N., Cardiovascular reflexes mediated by capsaicin sensitive cardiac afferent neurones in dogs, Cardiovasc. Res., 20 (1986) 897-906. 438 Stebbins, C.L., Smith, R.C. and Longhurst, J.C., Effect of prostaglandins on bradykinin-induced visceral-cardiac reflexes, Am. J. Physiol., 249 (1985) H155-H163. 439 Stein, J.H. (Ed.), Internal Medicine, 2rid edn., Little, Brown and Co., Boston, MA, 1987. 440 Stein, R.D., Genovesi, S., Demarest, K.T. and Weaver, L.C., Caps~cin ',re~.',ment attenuates the reflex excitation of sympathetic activity caused by chemical stimulation of intestina~ afferent nerves, Brain Res., 397 (1986) 145-151. 441 Stein, R.D. and Weaver, L.C., Multi- and single-fibre mesenteric and renal sympathetic responses to chemical stimulation of intestinal receptors in cats, J. Physiol. (Lond.), 396 (1988) 155-172. 442 Strassman, P., Mason, P., Moskowitz, M. _and Maciewicz, R., Response of brainstem trigeminal neurons to electrical stimulation of the dura, Brain Res., 379 (1986) 242-250. 443 Stulrajter, V., Pavlasek, J., Strauss, P., Duda, P. and Gokin, A.P., Some neuronal autonomic and behavioral correlates to visceral pain elicited by gall-bladder stimulation, Activ. Nerv. Sup. (Praha), 20 (1978) 203-209. 444 Sturge, W.A., The phenomena of angina pectons and their bearia~ ~v-'bii ,,~;~h~:x,~y v,'~'¢,,u~tcr-irritation,Brain, 5 (1883) 492-510. 4~4a Sugiura, Y., Terui, N. and Hosoya, Y., Differences in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers, J. Neurophysiol., 62 (1989) 834-840. 445 Sutton, D.C. and Lueth, H.C., Pain: experimental production of pain on excitation of the heart and great vessels, Arch. Intern. Med., 45 (1930) 827-867. 446 Swarbrick, E.T., Bat, L., Hegarty, J.E. and Williams, C.B., Site of pain from the irritable bowel, Lancet, i-ii (1980) 443-446. 446a Sylv6n, C., Angina pectoris. Clinical characteristics, neurophysiological and molecular mechanisms, Pain, 36 (1989) 145-168. 447 Taber, R.I., Greenhouse, D.D., Rendell, J.K. and Irwin, S., Agonist and antagonist interactions of opioids on acetic acid-induced abdominal stretching in mice, J. Pharmacol. E:~p. Ther., 169 (1969) 29-38. 448 Tagushi, H., Masuda, T. and Yokota, T., Cardiac sympathetic afferent input onto neurons in nucleus ventralis posterolateralis in cat thalamus, Brain Res., 436 (1987) 240-252. 449 Takahashi, M. and Yokota, T., Convergence of cardiac and cutaneous afferents onto neurons in the dorsal horn of the spinal cord in the cat, Neurosci. Lett., 38 (1983) 251-256. 450 Tattersall, J.E.H., Cervero, F. and Lumb, B.M., Effects of reversible spinalization on the visceral input to viscero-
somatic neurons in the lower thoracic spinal cord of the cat, J. Neurophysiol., 56 (!986) 785-796. 451 Tattersall, J.E.H., Cervero, F. and Lumb, B.M., Viscerosomatic neurons in the lower thoracic spinal cord of the cat: excitations and inhibitions evoked by splanchnic and somatic nerve volleys and by stimulation of brain stem nuclei, J. Neurophysiol., 56 (i986) 1411-1423. 452 Taylor, D.E.M., Reflex effects of slow bladder filling on the blood pressure in cats, Quart. J. Exp. Physiol., 50 (1965) 263-270. 453 Taylor, D.E.M., Afferent pathways and efferent mechanisms in the bladder viscero-vascular reflex, Quart. J. Exp. Physiol., 53 (1968) 262-272. 454 Taylor, D.E.M., Some observations on the effect of slow distension of the bladder and the rectum on cardiac output in the cat, J. Physiol. (Lond.), (1973) 100-101. 455 Theobald, G.W., Referred pain, in particular that associated with dysmenorrhea and labour: a preliminary report, Br. Med. J., 2 (1936) 1307-1308. 456 Thies, R. and Foreman, R.D, Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal afferent nerves, Exp. Neurol., 82 (1983) 1-16. 457 Thornburn, W., The sensory distribution of spinal nerve, Brain, 16 (1893) 355-374. 458 Tobey, J.C. and Weaver, L.C., Pressoreceptor modulation of renal but not splenic s)~rnpathetic reflexes, Am. J. Physiol., 252 (1987) R26-R33. 459 Tyner, C.F., Splanchnic nerve activation of single cells in the cat's postcruciate motosensory cortex, Exp. Neurol., 63 (1979) 76-93. 460 Uchida, Y. and Murao, S., Excitation of afferent cardiac sympathetic nerve fibers during coronary occlusion, Am. J. Physiol., 226 (1974) 1094-1099. 461 Uchida, Y. and Murao, S., Bradykinin-induced excitation of ~fferent cardiac sympathetic nerve fibers. Jpn. Heart J., 15 (1974) 84-91. 462 Ueda, H., Uchida, Y. and Kamisaka, K., Mechanism of the reflex depressor effect by kidney in dog, Jpn. Heart J., 8 (1967) 597--606. 463 Ueda, H., Uchida, Y. and Kamisaka, K., Distribution and responses of the cardiac sympathetic receptors to mechanically induced circulatory changes, Jpn. Heart J., 10 (1969) 70-81. 464 Vance, W.H. and Bowker, R.C., Spinal origins of cardiac afferenls from the region of the left anterior descending artery, Brain Res., 258 (1983) 96-100. 464a Vecchiet, L., Giamberardino, M.A., Dragani, L. and Albe-Fessard, D., Pain from renal/ureteral calcinosis: evaluation of sensory thresholds in the lumbar area, Pain, 36 (1989) 289-295. 465 Villanueva, L., Cadden, S.W. and LeBars, D., Diffuse noxious inhibitory controls (DNIC): evidence for postsynaptic inhibition of trigeminal nucleus caudalis convergent neurones, Brain Res., 321 (1984) 165-168. 466 Vogt, A., Vetterlein, F., Ri, H.D. and Schmidt, G., Excitation of afferent fibers in the cardiac sympathetic nerves
233 induced by coronary artery occlusion and injection of bradykinin. The influences of acetylsalicylic acid and dipyron, Arch. Int. Pharmacodyn., 239 (1979) 86-98. 467 Von Euler, C. and Sj~strand, T., The elicitafion of viscero-motor reflexes, Acta Physiol Y~:and., 14 (194"/) 363-372. 468 Waldrop, T.G., lwamoto G.A. and Ordway, G.A., Cardiovascular reflexes arising from the gallbladder and pancreas in spinal and decerebrate cats, Brain Res., 299 (1984) 358-362. 469 Waldrop, T.G., Rybicki, K.J., Kaufman, M.P. and Oralway, G.A., Activation of visceral thin-fiber afferents increases respiratory output in cats, Resp. Physiol., 58 (1984) 187-196. 470 Watkins, A.L., Reflex responses of the nictitating membrane and the blood pressure to distension of the bladder and rectum, Am. J. Physiol., 121 (1939) 32-39. 471 Weaver, L.C., Cardiac sympathetic afferent influences on renal nerve activity, J. Auton. Ncrv. Syst., 3 (1981) 253263. 472 Weaver, L.C°, Organization of sympathetic responses '.o distension of urinary bladder, Am. J. Physiol., 248 (1984) 236-240. 473 Weaver, L.C., Danos, L.M., Oehl, R.S. and Meckler, R.L., Contrasting reflex influences of cardiac afferent nerve during coronary occlusion, Am. J. Physiol., 240 (1981) H620-H629. 474 Weaver, L.C., Genovesi, S., Stella, A. and Zanchetti, A., Neural, hemodynamic, and renal responses to stimulation of intestinal receptors, Am. J. Physiol., 253 (1987) H1167Hl176. 475 Weaver, L.C., Macklem, L.J., Reimann, K.A., Meckler, R.L. and Oehl, R.S., Organization of thoracic sympathetic afferent influences on renal nerve activity, Am. J. Physiol., 237 (1979) H44-H50. 476 Weber, R.N., Blair, R.W. and Foreman, R.D., Effects of intracardiac injections of bradykinin on thoracic spinal neurons in the cat, Exp. Neurol., 78 (1982) 703-715. 477 Weiss, S. and Davis, D,, The significance of the afferent impulses from the skin in the mechanism of visceral pain: skin infiltration as a useful therapeutic measure, Am. J. Med. Sci., 176 (1928) 517-536. 478 Wennmalm, A., Chanh, P.H. and Junstad, M., Hypoxia causes prostaglandin release from perfused rabbit hearts, Acta Physiol. Stand., 91 (1974) 133-135. 479 Wernoe, T.B., Viscero-cutane Reflexe, Pfliigers Arch., 210 (1925) 1-34. .480 White, J.C., Sensory innervation of the viscera, Res. Publ. Ass. Nerv. Ment. Hlth, 23 (1943) 373-390. 481 White, J.C. and Bland, E.F., The surgical relief of severe angina pectoris, Medicine, 27 (1948) 1-42. 482 White, J.C., Garry, W.E. and Atkins, J.A., Cardiac innervation: experimental and clinical studies, Arch. Surg., 26 (1933) 765-786. 483 White, J.C. and Sweet, W.H., Pain and the Neurosurgeon: a 40 Year Experience, Thomas, Springfield, IL, 1963, pp. 525-589.
484 White, J.C., Verlot, M.G. and Ehrentheil, O., Neurogenic disturbances of the colon and their investigation by the colonmetrogram, Ann. Surg., 112 (1940) 1042-1057. 485 xtnaa;,.,,,~p,~ -~,.-,--,.-~-, J.G., Sensory innei-vation of the lungs and airways. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Voi. 67, Elsevier, Amsterdam, 1986, pp. 49-64. 486 Wid6n, L., Cerebellar representation of high threshold affercnts in the splanchnic nerves with observations on the cerebellar projection of high threshold somatic afferent fihre~ Acta Physiol. Scand., 117. Suppl. 33 (1955) 1-69. 487 Willis, W.D., The Pain System, Karger, Basel, 1985. 488 Willis, W.D., Visceral inputs to sensor pathways in the spinal cord. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 207-225. 489 Winning, A.J. and Widdicombe, J.G., The effect of lung reflexes on the pattern of breathing in cats, Resp. Physiol., 27 (1976) 253-266. 490 Woodworth, R.S. and Sherrington, C.S., A pseudaffective reflex and its spinal path, J. Physiol. (Lond.)~ 31 (1904) 234-243. 491 Woolf, C.J. and Wall, P.D., Relative effectiveness of Cprimary afferent fibers of different origins in evolOng a prolonged facilitation of the flexor reflex in the rat, J. Neurosci., 6 (1986) 1433-1442. 492 Woolf, H.G., Hardy, J.D. and Goodell, H., Studies on pain. Measurement of the effect of morphine, codeine and other opiates on the pain threshold and an analysis of their relation to the pain experience, J. Clin. Invest., 19 (1940) 659-680. 493 Woollard, H.H. and Carmichael, E.A., The testis and referred pain, Brain, 56 (1933) 293-303. 494 Woollard, H.H., Roberts, J.E.H. and Carmichael, E.A., An enquiry into referred pain, Lancet, i (1932) 337-338. 495 Wurster, R.D. and Randall, W.C., Cardiovascular responses to bladder distension in patients with spinal transection, Am. J. Physiol., 228 (1975) 1288-1292. 496 Wyngaarden, J.B. and Smith, Jr., L.H. (Eds.), Cecil's Textbook of Medicine, 18th edn., Saunders, Philadelphia, PA, 1988. 497 Wyss, J.M. and Donovan, M.K., A direct projection from the kidney to the brain~tem, Brain Res., 298 (1984) 130134. 498 Yamamoto, S., Araki, K. and Kikuch/, M., Abdominal muscle reflexes of pelvic nerve origin in cats, Exp. Neurol., 4 (1961) 345-357. 499 Yokota, T., Masuda, T., Tagushi, H. and Koyama, N., Viscerosomatic convergence onto nociceptive neurons in the shell region of nucleus ventralis posterolateralis. In: R.F. Schmidt, H.-G. Schaible and C. Valhe-Hinz (Eds.), Fine Afferent Nerve Fibers and Pain, VCH Verlagsgesellschaft, Weinheim, 1987, pp. 427-437. 500 Yokota, T., Nozuma, N°; Nishikawa, Y., Koyama, N., Tagushi, H., Masuda, T., Nomura, T. and Asato, F., Thalamic mechanisms of nociception: nociceptive neurons in VPL of cat thalamus. In: H. Tagushi, Y. Oomura and "
234 M. Ito (Eds,), Biowarning System in the Brain, Univ. Tokyo Press, Tokyo, 1988, pp. 17-30. 50_' Zolliag¢.,', R., Oi,~,~:rvations following distension of the gallbladder and common duct in man, Proc. Soc. Exp. Biol. Meal. (NY), 30 (1933) 1260-1264.
502 Zollinger, R., Significance of pain and vomiting in chole. lithiasis, JAMA, 105 (1935) 1647-1652. 503 Zollinger, R. and Walter, C.W., Localization of pain following faradic stimulation of the common bile duct, Proc. Soc. Exp. Biol. Med. (NY), 35 (1936) 267-273.
167
PAIN 01600
Basic Section Review A rtide
Visceral pain: a review
experimental studies
T.J. Ness a,b and G.F. Gebhart b Departments of a Anesthesia and b Pharmacology, College of Medicine, Unioersity of lowa, lowa City, 1,4 52242 (U.S.A.) (Accepted for publication: 15 January 1990)
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anatomy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrophysiological studies of visceral primary afferents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Adequate visceral stimuli and nociceptive responses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Organization of the review . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Electrical stimulatior as a noxious visceral stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanical stimuli as noxious visceral stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ischemia as a noxious visceral stimulus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemical stimuli as noxious visceral stimuli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Final summary and comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
167 169 173 174 175 178 188 205 208 214 218 218
Summary This paper reviews clinical and basic science research reports and is directed toward an understanding of visceral pain, with emphasis on studies related to spinal processing. Four main types of visceral stimuli have been employed in experimental studies of visceral nociception: (1) electrical, (2) mechanical, (3) isehemic, and (4) chemical. Studies of visceral pain are discussed iu relation to the use and 'adequacy' of these stimuli and the responses produced (e.g., behavioral, pseudoaffective, neuronal, etc.). We propose a definition of an adequate noxious visceral stimulus and speculate on spinal mechanisms of visceral pain. Key words: Pelvic; Thoracic; Abdominal; Noxious; Afferents; Adequate stimuli; Pseudoaffective; Splanchnic; Clinical; Behavior; Spinal dorsal horn
Introduction
Clinically, pain is classified physiologically as superficial, deep or neuropathic. Superficial pain
Correspondence to: Dr. G.F. Gebhart, Department of Pharmacology, Bowen Science ~uilding, University of Iowa, Iowa City, IA 52242, U.S.A.
arises from the stimulation of cutaneous structures, d~.ep pain from stimulation of muscle, fascia, joints, bone, vascular structures and the viscera, and neuropatlfic pain from a disturbance of function or pathological changes in nervous tissue. Deep pain is of greatest clinical importance since pain from deep structures constitutes the majority of pain treated by the medical community. As opposed to superficial pain arising from cutaneous
0304-3959/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
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structures, which is well localized and evokes specific protective responses such as flexion reflexes, deep pains are characterized by poor localization, tonic increases in muscle tone, and a propensity to evoke strong autonomic responses such as changes in respiration, heart rate and blood pressure. Deep pains are also thought to evoke stronger emotional responses than superficia~ pains. As the intensity and duration of the stimulus increase, the subjective localization of deep pain becomes more generalized. That is, pain will radiate and be perceived as originating from a larger area, although the pain may become more intense at one site. Examples are pain originating from an inflamed joint, which may make an entire limb ache, or the pain typical of myocardial infarction: a dull pain/pressure located substemally which may spread to involve the entire chest and radiate to the shoulders, neck, jaw and down the ulnar aspect of the arms [446a]. Deep pains from bilateral structures (e.g., limbs, chest walls) are lateralized to one side and are roughly localized so that probing of sites that produce pain can localize 'point tenderness.' This is in contrast to deep pains from most of the viscera, which derived embryologically from midline structures (e.g., heart, gut, liver). Visceral pains are referred or 'transferred' to somatic (nonvisceral) structures near the midline, are more diffuse than other deep pains, and are not amenable to the localization of precise point tenderness until the pain-producing process (e.g., infectioninflammation) spreads and involves bilateral structures (e.g., the abdominal wall peritoneum). In addition to the phenomenon of referred pain, cutaneous and deep ti:~sue hyperalgesia also occur in association with visceral pain [e.g., 464a]. That is, skin and dee~ ti ~-.,cs become sensitized by an unknown process a~d previously innocuous somatic stimuli (e.g., stroking of the skin) may become painful. Because of its protean qualities, visceral pain is generally separated as a special case of deep pain. Pain originating in ore viscus cannot be easily differentiated from pain originating in another viscus by the quality, localization or intensity of sensation alone. Determination of the etiology of visceral pain is thus based on its generalized loca-
tion and clinical data such as rate of onset, aggravating factors and associated pathology (e.g., increased white blood cell count). A prime example of the poor differentiation of pain from a specific viscus is that of acute appendicitis. Based on the quality of the pain and locations where pain is sensed, the abbreviated differential diagnosis for this pathological condition listed in Cope's Diagnosis of the Acute Abdomen [428] includes the infection, inflammation, perforation/rupture, distension or torsion of the gallbladder, stomach, small intestine, colon, kidneys, ureters, pancreas, ovaries, fallopian tubes, psoas muscles or rectus muscles. Descriptions of some visceral pains have b~'en associated with specific etiologies. For example, pain from pancreatitis is typically intense and bores through to ,be back, pain from a dissecting aortic aneurysm is throbbing, pain from the intestines is crampy or colicky, and the pahl of a peptic ulcer is achy or burning. Unfortunately, visceral pain is unreliably 'typical' and the verbal descriptors of pain originating from a single viscus have been demonstrated to include words from every sub~oup of the McGill Pain Questionnaire [392]. The problem clinically is that pain originating from any of the viscera can be confused with pain from most other viscera end any statement that pain originating from a specific viscus is always of o,le type or localized to one body site demonstrates ignorance of the clinical experience of pain. For example, Staniland et al. [434] studied 600 patients presenting with an acute abdomen and reported that only two-thirds of the patients presented with symptoms that were 'typical' for the later determined etiology of their pain. There exists a wealth of clinical and older experimental literature which has addressed the subject of visceral pain and in recent years there has developed a renewed interest in behavioral, physiological and neurophysiological responses to noxious visceral stimuli. Investigations of visceral p~'m have addressed 5 main points [110]: (1) the nature of the adequate stimulus; (2) the site of its action; (3) the distribution of 'pain' nerve-endings in the viscera; (4) the peripheral and central nervous pathways which lead from ,dscus to sensorium; and (5) the 'mechanisms,' ~ t h physical and psycholo~cai, involved in die reference or localiza-
169
tion of visceral pain. The present paper summarizes some of the experimental literature related to visceral pain and suggests directions for future investigation.
Anatomy Viscerotomes
Just as cutaneous dermatomes are arranged according to the original arrangement of :issues in the embryo (Fig. 1), so too are ' viscerotomes' also arranged according to the original embryological location of the viscera. Viscerotomes are defined by patterns of evoked or pathological referred pain and by cutaneous and deep tissue hyperalgesia and the relief thereof provided by neurosurgical or local anesthetic procedures described in the clinical literature (Fig. 1). The heart, lungs, gut, liver, spleen, pancreas, gallbladder and urinary bladder all begin as midline tubes of mesoderm and endoderm which subsequently become convoluted, outpouched and thickened. The originally straight fore-, mid- and hindgut tubes lengthen, form loops and rotate 270 ° on a centred axis formed by the blood supply to the viscera. As a result, structures that originally were in the lower abdomen end up in the upper abdomen (and vice versa) and a somatotopic progression of the viscerotomes may not seem obvious. The viscera have a complex peripheral nervous system that allows for a wide variety of local autonomic functions. There is a dual innervation of the viscera, involving both cranial and spinal nerves, with secondary internet~rons in the medullary [e.g., 124,423,442] and spinal dorsal horns (see neuroanatomic references in Table It. Whereas cutaneous structures have sensory neurons that are located only in cranial nerve or dorsal root ganglia, the viscera have additional sensory neurons with cell bodies in and on the viscera themselves, in ganglia near the viscera (i.e., the prevertebral ganglia such as the celiac or inferior mesenteric ganglia), and may have cell bodies in the sympathetic chain along the vertebral colunto (paravertebral ganglia). Primary afferent neurons which transmit visceral sensory information to the spinal cord have cell bodies that reside in
the dorsal root ganglia. These primary afferents have distal processes that travel through the paravertebral ganglia, through the prevertebral ganglia and eventually have sensory endings in the viscera themselves. Large aggregations of these afferents are found in conjunction with motor fibers of the p~asympathetic nervous system in the pelvic nerve and with motor fibers of the sympathetic nervous system in numerous nerves. Fig. 2 is a schematic diagram of the gross anatomy of the visceral nerves of the human. Peripheral to the prevertebral ganglia, the continuation of visceral nerves is typically named by the organ innervated (e.g., renal nerve, rectal branch of the pelvic nerve). The phrenic nerve, originating predominantly at the C3-C5 spinal segments, is an additional pathway for visceral afferents from the diaphragm, liver, gallbladder, pericardium and pancreas [9,206,271]. The visceral nerve pathways identified above (i.e., through prevertebral ganglia, etc.) are based on gross anatomy and classical nerve degeneration studies [e.g., !50,258] that used light transmission microscopes to trace myelinated nerve fiber pathways. In recent years, anatomists have reexamined these earlier findings using the electron microscope and retrogradely transported neuronal tracers such as horseradish peroxidase and fluorescent dyes. Predictably, some previous assumptions of nerve pathways based upon gross anatomy and nerve degeneration studies have been found to be incorrect. For example, Hulsebosch and Coggeshall [219], using neuroablative and electron microscopic techniques, demonstrated that the pelvic nerve contains numerous sympathetic efferent fibers, a previously unsuspected finding. New visceral pathways also have been found. Sensory neurons with cell bodies in the rectum projecting directly to the spinal cord via the Lk,rsal roots have been reported [138a]. Another example is the existence of ventral root visceral afferents identified by neuroanatomical and dectr,,physiological techniques [106>107,109,165,324, 4121. The use of neuronal tracers has allowed for a precise, quantitative description of the spinal segmental distribution of afterents frot~l various organs, in various nerves, in numerous species.
170
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Fig. 1. Human viscerotomes: spinal segments m which visceral sensations are processed. A: illustration of human embryo and original relation between location of viscera and developing spinal nerves. B: examples of dcrmatomes corresponding to listed spinal segments. C: diagrammatic representation of presumed viscerotomes in humans as determined by the following: sites of 'referred" pathological pain ( ~ indicates typical dermatomes of referral listed in refs. 428, 439, 496; thickness of line relates to the frequency of occurrence); sites of cutaneous hyperalgesia associated with visceral disease ( - - - as in refs. 207, 286, 457); neurosurgical destruction of dorsal roots or local anesthetic blocks which lead to relief from pathological visceral pain ( . . . . . . , * indicates splanchnectomy effective in pain relief; from refs. 227, 410, 480-483, Lawen, 1923 and Hansen, 1963 both cf., 224); and sites of referred experimental pain ( . . . . . . , refs. in Table I). Abbreviations: Liv., liver; pane., pancreas; CI-TI-LI-S l, cervicalthoracic-lumbar-sacral spinal segments.
Studies in cats and rats are summarized in Figs. 3 and a, respectively. A similarly complete figure for the primate cannot yet be constructed since relatively few data are available [335].
Distribution of visceral afferents in the spinal cord A consistent finding of neuroanatomical studies of visceral afferent projections to the spinal cord is that they terminate predominantly in lamina I,
171
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deeper laminae (e.g., V and X) and adjacent to autonomic motor nuclei [130]. Visceral afferents appear to form a shell-like embracement of the dorsal horn with medial and lateral pathways that are 'repelled' by laminae IIi and III [349]. This has been documented for the greater splanclmic nerve [91,254,349], the colonic nerve [325], the least splanclmic nerve [347], the hypogastric nerve [326,347], the inferior cardiac nerve [256], the left renal nerve [255] and the pelvic nerve [324,334, 335]~ This disu~bution of primary afferents is consistent with electrophysiological studies demonstrating that spinal neurons excited by visceral stimuli are located predominantly in laminae I and II o and deeper laminae (e.g., IV-VII and X), but are largely absent from laminae IIi and III [e.g., 16,24,26,59,88,89,245,319,449]. The distribution of visceral primary afferents is similar to what has been demonstrated for fine afferents from other deep tissues such as muscle and joints [e.g.,
114,315], both of which are different from the sites of termination of afferents in nerves containing cutaneous afferents [e g. 2,91,349]. Afferents from cutaneous structures have numerous projections to all dorsal horn laminae with fine afferents terminating predominantly in laminae I and II o. Recently, the central terminals of intracellularly labeled axons of slowly conducting visceral and cutaneous afferents were compared in the guinea pig [444a]. Visceral afferents from the celiac ganglion had both ascending and descending central branches with collaterals that terminated ipsilaterally in laminae I, II, IV, V and X; some also gave collaterals into the contralateral laminae IV, V and X. Terminals of fine cutaneous affcrents, on the other hand, were concentrated in laminae I and II with a highly circumscribed ~nest-like' distribution (400 vm rostrocaudal distribution). Numerically, visceral afferents have been estimated to compose 5-15% of the neuronal
172
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cell bodies in the dorsal root ganglia at the spinal segments receiving maximal visceral afferent input [92,254,349]. This is out of proportion to the relative number of spinal neurons which respond to Cervical Thoracic Lumbar Sacral I~1213141sl s]-~ el 11213141Sls171a19hob lh 2hal I 1213141s[ el t121 xl 4 ~J Phrenlc n. Greater Splanchnic n. Least $planchnlc/Hypogastrlc
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visceral afferent input at those same spinal segments, estimated to be 56-75% [e.g., 97], supporting the assertion that visceral afferent terminals are widely distributed in the spinal cord. Some visceral afferents also have been identified as projecting directly to the brain-stem [243,254,324, 347,349,429,497].
Dichotomizing primary afferents Another interesting finding is the possible existence of a small number of dichotomizing afferent fibers with sensory endings in both viscera and somatic structures. Pierau et al. [383] reported that 1.5-2.4% of the cell bodies of visceral afferents traveling in the greater splanchnic nerve of the cat could be double-labeled with retrogradely transported fluorescent dyes applied to the greater splanchnic nerve and a somatic nerve. Based on an observation by Alles and Dam [11], McNeill and Burden [309] reported that 7-15% of neurons labeled by injecting a fluorescent dye into the pericardial sac of the rat and located in the C8-T1 dorsal root ganglia were double-labeled by another fluorescent label applied to the left ulnar nerve. Similar convergence between the diaphragm and shoulder muscles has been reported [264]. The methodology of some of these studies was called into question by Dalsgaard and Ygge [122], who failed to identify more than a few double-labeled neurons receiving input from the splanchnic and thoracic spinal nerves; these investigators concluded that visceral and somatic afferents were separate populations. Supporting evidence for the existence of dichotomizing fibers has been given by electrophysiological experiments, demonstrating the existence of single afferent fibers that can be electrically activated from the pelvic and pudendal i~erves [198] or from thoracic visceral and somatic nerves [36]. The function of these dichotomizing fibers is unknown; they may contribute to the mechanism of referred pain [430,479]. However, fmlctional sensory endings have yet to be demonstrated for 'dichotomizing' afferent fibers. Neurotransmitters in visceral primary afferents Numerous neurotransmitters have been identified in visceral primary afferents, including sub-
173
stance P and calcitonin gene-related peptide (CGRP) [e.g., 321]. An in-depth discussion of these neurotransmitters is beyond the scope of this review and has been well reviewed elsewhere [e.g., 131,138]. An interesting finding by Sharkey et al. [424; personal communication] is the existence of "clusters' of substance P and CGRP immunoreactive nerve te~:,~nals of visceral origin in lamina V of the sp; ~ c~rd. This finding is of especial interest to eleetrophysiologists who have noted that spinal neurons excited by visceral stimuli often are found in clusters [e.g., 60,97; Ness and Gebhart, unpublished] and correlates with findings of other investigators [130] that there is a periodicity of 300-1000/~m in the distribution of visceral primary afferents to laLnina V. Most neurotransmitters identified in visceral primary afferents also have been found in somatic primary afferents. However, vasoactive intestinal polypeptide has been suggested to be selective, if not specific, for visceral afferents, particularly those from pelvic organs [e.g., 216,235].
Functional identification of visceral afferent pathways An alternative to the neuroanatomical demonstration of primary afferent pathways is the 'functionar identification of these afferents. Functional identification derives from the stimulation of visceral afferents electrically or with other stimuli (e.g., distension or injection of algesic chemicals) in order to produce reflex responses such as changes in heart or respiratory rate and subsequently to abolish/attenuate these responses by selective neural lesions. The advantage of functional studies over direct neuroanatomical studies is that they may also give evidence of the sensory modalities of the afferents. That is, although there may exist afferents from the gallbladder at numerous spinal segments, the afferents encoding for distension of the gallbladder may enter the spinal cord at only a subset of these. As is demonstrated in Fig. 3, functional studies are in general agreement with neuroanatomical studies and in many cases are the only studies reported which define nerve pathways from certain viscera.
Electrophysiological studies of visceral primary afferents
Electrophysiologically, primary afferent neurons can be classified according to their response to natural stimuli, according to their conduction velocity, which suggests the presence or absence of myelination and diameter of nerve fiber, or according to their central sites of projection. Few electrophysiological studies have examined the central sites of projection of functionally identified ,visceral afferents and so the work of Downman and Evans [145] and Schramm and associates [243,244,429] deserves special notice in that these investigators characterized visceral afferents for their responses to natural stimuli, their conduction velocity and their central sites of termination, which were both spinal and medullary w~th axons traveling rostrally in the dorsal columns. Numercus visceral afferents have been characterized for conduction velocity,and responses to natural stimuli and the characteristics of these neurons will only be brieflydiscussed as this literature has been reviewed elsewhere [29,222,224, 253,265,268,290,312,313,330,331,368,416].In general, most visceral afferents have relatively slow conduction velocities(i.e.,are thinly myelinatcd or unmyelinated nerve fibers). The relation of activity in primary afferents to visceral pain sensation is still poorly understood, due in part to the absence of agreement on definition of an adequate, noxious, visceral stimulus. The most sigrdfieant result of quantitative electrophysiological studies of visceral afferents is the virtual absence of specific nociceptors. That is, primary afferents dedicated to nociception with high thresholds for mechanical activation and/or selective chemosensitivity have not been identified as a distinct subclass of visceral afferents, alt h o u ~ afferents of differing sensitivities have been described [339]. General!,y, visceral afferents such as those from the colon traveling in the least splanchnic nerves of the cat have been found to be polymodal, giving excitatory responses to bradykinin, KCI, hypertonic saline, ischemia and to colonic distension with intraluminal pressure thresholds for response near 0 ram Hg [64,205]. Sirrfil~r
174
polymodal afferents from the testis [253] and from the heart [290] have been characterized, which has prompted various investigators to assert that visceral pain is due to the intensity or pattern of visceral primary afferent activation [e.g., 224,290]. One general criticism of most studies of visceral afferents is that they typically have recorded from sensory fibers in peripheral visceral nerves. Sensory fibers which do not project to the spinal cord, but only to para- or prevertebral ganglia [e.g., 239], are :herefc,re contained in these samples of nerve fibers and may constitute a majority of the sensor)' fibers present. Since these fibers are likely involved in local autonomic processing of non-noxious stimuli, the failure to identify specific visceral nociceptors may reflect their proportionately small number in the periphery. Another consideration is that virtually all reports to date have studied 'normal' non-inflamed tissue, a circumstance where nociceptors may be silent (see below). Several studies, however, have suggested that specific visceral nociceptors may exist since visceral afferent fibers with high mechanical thresholds for activation have been identified. Cervero [87] characterized 2 classes of afferents from the gallbladder and biliary tract of the ferret: one population was excited at low pressures of distension and the other was not excited until the gallbladder was distended by pressures sufficient to evoke cardiovascular responses. Earlier, Gernandt and Zotterman [182] studied gastrointestinal 'nociceptors' with high mechanical thresholds for activation in multifiber recordings of afferents in mesenteric nerves, as did Clifton et al. [106] in recordings from lumbosacral ventral root afferents. Morrison and associates [164,166, 329,330] also may have identified gastrointestinal nociceptors wher~ they recorded from visceral afferents that responded vigorously only to stimuli which produce pain in humans (i.e., contractions or overdistension of the large intestine and traction on the mesentery). While these studies support the existence of visceral nociceptors,, it may be that the high threshold group of afferents from the gallbladder characterized by Cervero or the gastrointestinal 'nociceptors' charactedzed by others may be the tail of a normal distribution of a single population of non-specific, polymodal
visceral afferents as suggested by J~fig [224; personal communication]. Alternatively, specific nociceptors may exist for some (e.g., gallbladder), but not all viscera or be normally silent. There exist afferent fibers from deep structures (e.g., joints, viscera) which can be activated by electrical stimulation but not other, natural stimuli (i.e., they are 'silent' normally). In circumstances of experimentally induced inflammation, these silent nociceptors can be activated by stimuli previously ineffective. Thus, specific nociceptors in deep tissue may exist but only become evident when tissue pathology is present. Experimental studies, of course, are generally carded out in 'normal' subjects which would significantly underestimate the presence of specific nociceptors since tissue pathology is not present.
Adequate visceral stimuli and nociceptive responses Defining an adequate noxious stimulus for studies of visceral nociception has been a significant obstacle to quantitative experimental studies of visceral pain. Adequate stimuli are those that optimally and/or naturally produce a given sensation. Sherrington [425] defined 'nocuous' stimuli as those that produced tissue damage or nredicted tissue damage. For cutaneous structures, this definition is consistent with stimuli painful to humans. However, non-inflamed viscera in humans often can be cut or burned (tissue damaged) without producing pain. This prompted numerous investigators, who performed procedures utilizing local or regional rather than general anesthesia [e.g.,286,287; Lennander, cf., 273], to claim that the viscera were insensate and that visceral sensations resulted from the irritation of the parietes (lining of chest/abdominal wall). However, many of these early studies were confounded by the use of morphine as a prctreatment or excessive doses of cocaine as a local anesthetic. Numerous subsequent studies have clearly established that pain can originate from the viscera, but that cutting, burning or highly localized mechanical stimuli may not be adequate stim,.di. For example, Kinsella [241] evoked reports of pain by squeezing the entire length of isolated, inflamed appendices.
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Pinch of a 2-3 mm stretch of the same appendices using a fine forceps in the same patients caused no pain. Consequently, noxious visceral stimuli are defined here as those stimuli, preferably natural, which produce visceral pain in humans and behavioral responses in other animals typically associated with tissue damaging cutaneous stimuli in animals (e.g., escape, avoidance, etc.). Ideally, an adequate noxious visceral stimulus also should be reproducible, easily controlled to provide quantifiable, graded stimuli, and minimally invasive to limit the influence of experimental methodology on the resuKs. A nociceptive response to an adequate noxious stimulus is one that is consistent with what is observed clinically in humans and occurs in response to that stimulus or other adequate noxious stimuli. Commonly measured nociceptive responses are the pseudoaffective responses characterized by Sherrington and coworkers [425]. Pseudoaffective responses are brain-stem or spinal reflexes which suggest an emotional or affeetive response to tissue-damaging cutaneous stimuli or, by the above definition, to noxious visceral stimuli. These responses include flexion/withdrawal and head-turning with lateralized somatic stimuli and grimacing, vocalization, cardiovascular changes, respiratory changes and generalized or regional muscle contractions with non-lateralized somatic or visceral stimuli [490]. Pseudoaffective responses cease when the noxious stimulus is terminated. Examples of cardiovaseu-
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i
Fig. 5. Pseudoaffective responses. Examples of visceromotor (top, electromyogram (EMG) of external oblique musculature), cardiovascular (middle recordings) and respiratory (bottom, plethysmographie record) responses to colorectal distension (80 ram Hg, 20 sec) in an awake unanesthetized rat [see 342 for full characterization].
lar, respiratory and visceromotor pseudoaffective responses to noxious colorectal distension in the rat are illustrated in Fig. 5.
Organization of the review Experimental studies of visceral nocicepfiot~ have used as stimuli electrical shocks, mechanical distortion (e.g., distension of hollow organs), ischemia and algogenic/irritant compounds. Given the importance of the stimulus, experimental studies of visceral nociception are discussed under the headings of these 4 stimuli rather than by organ. Studies in man and those in other animals measuring behavioral, autonomic and electrophysiological responses are reviewed. Because the modulation of responses in animals is often used to define a stimulus/response as noxious/nociceptive, studies related to the modulation of visceral pain are also considered. Subheadings will allow the.reader to focus readily if desired. A listing of selected references by organ is given in Table I. The review is limited to studies employing mammalian species, although numerous interesting results have been noted in amphibians and reptiles [e.g., 81]. This review will only briefly discuss studies related to the activities of preganglionic spinal autonomic motor neurons that receive numerous visceral and somatic inputs [e.g. 132,223]. Discussions of cutaneous receptive fields of spinal neurons will use the class 1-3 terminology where neurons are defined as class 1 if only excited by non-noxious stimuli applied in their cutaneous receptive fields, class 2 if excited by both noxious and non-noxious stimuli, and as class 3 if only excited by noxious stimuli. This nomenclature is not ideal since it does not take into account inhibitory cutaneous receptive fields, responses to stimulation of non-cutaneous tissues or gradation of stimuli/responses; it does, however, allow for a qualitative comparison of the studies performed to date. What constitutes a noxious stimulus in nonhuman animals is always arguable and was often not defined in many of the studies described in tiffs Jeview. Based on statcments in the methods sections of studies from various laboratories, non-
Adson, Leriche, Foerester (cL, 273, 391)
141,494, Lerich~ Jonnesco (cL, 273,391)
267,405
Thoracic visceral nerves
Pelvic visceral
48,63,66,7% 101, 137a, 240 262,278,327, 391,492
Small intestine
Stomach
41, 46, 51, 101, 102, 209, 240, 251, 278, 327, 332, 373, 374, 384, 391, 395, 477 63, 66, 80, 332, 391
Esophagus
llerves
ilerves
Abdominal visceral
Human
210,348
43-45,198, 235, 301, 324-326, 334, 335, 347
15Z191,25~ 264,361,411
36, 91, 92, 122 153, 254, 349, 383
Neuroanatomic
Spinal: 192 Other: 82, 116, 226, 380
85,151,226
180,181
Spinal: 14-17d, 21, 24, 27a, 86-90, 94-98, 159, 170, 187, 188, 199, 200, 245, 372, 385, 409, 421, 422, 450, 451, Other: 5, 12, 13 82, 85, 143, 145, 303, 351-355, 378-380, 406, 407, 459, 486, 500 Spinal: 18-27, 57-61, 68, 69, 99 100, 168, 169, 171, 172, 192a, 214, 449, 456, 476 Other: 448, 499, 5OO 129, 132, 133, 307, 308, 500
Neuronal
146,151, 194, 281,283-285, 302, 310, 387, 420, 438 65, 104, 146, 147, 174, 194, 201, 202, 231, 237, 269, 274, 310, 311, 360, 363, 414, 420, 438, 440, 441, 474
146,415
4, 261,419
4, 74, 248, 293, 294, 381,471
1, 4, 6, 7,~ 105, 125, 146, 228, 370
Cardiovascular
146, 322
146, 194, 317, 322
34, 111, 112 133a, 146, 147, 194, 274, 317, 322, 467
194, 322, 413, 420, 469
34, 47, 117, 191a, 194, 322, 388, 413, 420
77,175,176, 317,498
322,415
4,175,176, 418
77,211
8, 33, 34, 40, 77, 105, 125, 144, 146, 147
4, 7, 33, 34, 125
4,211
Visceromotor
Respiratory
Pseadoaffective responses
SELECTED REFERENCF~; TO EXPERIMENTAL STUDIES OF VISCERAL PAIN LISTED BY NERVES/ORGANS
TABLE I
147, 206, 310
206, 310
206
4
4, 37
Nict./pupil. a
52,101,120, 140,179,212, 266, 271, 299, 300,332, 359, 390, 391,420, 501-503 431,493 71a, 225,247, 455
Biliary system/liver
10, 221,446a
Heart, lungs and related structures
119 12,, 309 464
49, 242, 336
9, 42, 220, 289
103,139,255
3~ 142
138a, 336, 343
Spinal: 18, 22, 25, 27, 57, 58, 60, 61, 68, 69, 99, 171,456, 476 Other: 53-56
233,319 133,250,389, 401,402 Other: 217
20, 23, 86, 89, 158,160,371
69,73,93, 129o132,133, 151,158,159, 215, 232,305, 307, 308, 319 Spinai:14-17d, 27a, 214,245
Spinal: 73, 129, 132, 133, 158160, 215, 307, 308, 340, 341, 343-346 Other: 151, 177
a Nict./pupil. indicates nictitating membrane or pupillary response (e.g., dila~ion).
328, 391
Pancreas
Spleen
Male reproductive Female reproductive
358, 391,464a 475
63,79,136,149, 155,189,213, 229,230,236, 240,241,262, 263,272,278, 327,391,397-399 446,484 120,134,193 337,391,495
Kidney and ureters
Urinary bladder
Colon/rectum
75,105,146, 194, 275, 311, 458 146, 274, 364, 414,468 71,84,156,157, 190,192a, 194, 2O4,234,252, 289, 293, 294, 296, 339, 356, 365,366,394, 435-437,445
233,320 146,175, 25;
1, 16-17d, 67, 74, 185, 224a, 249, 260, 37~, 432, 462, 490 23, 35, 86, 87, 89,119, 194, 322, 351, 362, 364, 420, 438, 443, 468, 490
151, 175, 186. 333, 419, 426, 452-454, 470, 472
123,151,175, 342,454,470
70,234,298, 322,323,376, 445, 481,482
7, 274
194,275,322
233,320 175,257
126,128,167, 194,322, 413, 420,443,469
322
]54,175,31~ 333,418
175,322,388
70, 234, 298, 322, 323, 376, 445, 481,482
146
146, 194, 317, 322
115, 146, 175
33, 34, 194, 443
317, 322, 490
3, 154, 175, 305, 306, 314
115,123,175, 227,288,316318,322,342, 433,490
70
206
206
206
470
206, 470
178
noxious stimuli include hair movement and fight pressure (e.g., brush, air puff) and noxious stimuli included pinch, crush, pin-prick and heat, all presumably at intensities sufficient to produce pain in the investigators. The terms 'visceral' and "somatic' will be used throughout this revie~v; somatic refers to all structures that are not internal organs and includes skin, muscle, joints, bone and connective tissue. The oral and nasal cavities, pharynx, vaginal introitus, outer urethra and anal canal all fall within a gray zone of the visceral or somatic distinction and so are generally not discussed.
Electrical stimulation as a noxious visceral stimulus
General Electrical stimulation of isolated nerves or organs is a reliable reproducible stimulus, but is not specific for any sensory modality. It has been suggested [e.g. 90,97] that spinal neurons excited by visceral afferents to the thoracic spinal cord traveling with sympathetic motor fibers can only be excited by noxious intensities of stimulation. If this assertion is correct, then electrical stimulation of these visceral nerves is ideal as a noxious stimulus since its non-specificity becomes irrelevant; excitation equates with nociception. Support for this simple assertion is given by electrophysiological evidence that only fine afferents from the viscera terminate in the spinal cord. Since fine afferents are assumed by many to carry information related only to nociception, a logical extension of this assumption is that all spinal neurons excited by electrical nerve stimulation are receiving noxious visceral inputs. 'Non-noxious' conscious sensory events, such as pressure or movement of gas in the bowel, must therefore be (1) due to pathways that travel through, but do not terminate in the spinal cord (e.g., dorsal column pathways); (2) actually 'painful' but not recognized as such; (3) due to activation of somatic abdominal wall sensory receptors; or (4) due to the activation of visceral sensory fibers travding in conjunction with parasympathetic motor fibers (e.g., vagus nerve). Numerous visceral sensations (e.g., stomach, rectal or bladder fullness, nausea) do travel
by such 'non-spinal' routes [488]. However, reports of spinall~ mediated, presumably non-nociceptive reflexes evoked by the natural, physiological stimulation of visceral afferents traveling in conjunction with sympathetic motor fibers argue that not all spinal processing of visceral afferent input is nociceptive [e.g., 228,367]. Numerous electrophysiological studies employing more natural stimuli such as probing of the heart [e.g., 57], distension of the gallbladder [20,23], distension of the urinary bladder [133,307,308] or distension of the c o l o n / r e c t u m [307,308,340,343,345] have demonstrated that there exist spinal neurons excited by presumably non-nociceptive intensities of visceral stimulation. With the caveat that experimental manipulations might make visceral primary afferents a n d / o r spinal visceral nociceptive neurons 'hyperalgesic,' and hence responsive to previously non-noxious intensities of visceral stimulation, the assertion that visceroceptive neurons in the spinal cord respond only to noxious intensities of visceral sensation is an overgeneralization as non-nociceptive, visceral inputs certainly can result in visceral sensation. Although electrical stimulation of the main visceral nerves provides an artificial stimulus which is neither organ- nor modality-specific, ample evidence for the utility of electrical stimulation as a noxious stimulus is given by human studies in which electrical stimulation of visceral nerves [Adson, cf. 391; Leriche, Foerester and Jonnesco, cf., 273; 141,267,405,494] or of the viscera themselves (biliary system [391,503], kidney/ureters [358,391], pancreas [391], gastrointestinal tract and associated membranes [66,78,391]) has consistently demonstrated that pain can be produced in most patients when the intensity of the electrical stimulation is sufficient to activate small diameter afferent fibers. Non-painful sensations also have been noted with electrical stimulation [e.g., 405], but electrical stimulation of visceral nerves without current spread to somatic tissues cannot be ruled out as a possible confounding factor. In humans, pain secondary to electrical stimulation of the various viscera was localized to regions consistent with what is observed in pathological referred pain. In addition to the effects of direct activation of visceral primary afferents, electrical stimulation
179
of the stomach or Oaodenum has been noted to produce spasm of these organs [66], which itself may produce pain. The characterization of spinal neurons responsive to visceral nerve electrical stimulation includes their location, rostral projections, conduction velocity of primary afferent input and characterisfcs of somatic input. A limitation of studies employing electrical stimulation of visceral afferents is that they do not allow for an assessment of changes in the sensitivity of the primary afferents due to peripheral mechanisms (e.g., inflammation), which clinically appears to be a major mechanism related to the etiology of pathological visceral pain. Experimental studies in which visceral nerves were stimtlated to produce neuronal or pseudoaffective responses can be grouped into 3 categories according to the nerves stimulated: abdominal visceral nerves, thoracic visceral nerves, and pelvic visceral nerves. As these studies are numerous, each category will be subgrouped according to the index of measurement (i.e., reflex or neuronal indices). Abdominal visceral nerves Reflex indices. Electrical stimulation of the greater (major) splanchnic nerves (left and right) has been commonly employed in studies of visceral sensation. These nerves contain afferents from most of the gut, the biliary/hepatic systems, the pancreas, the spleen, the kidneys, testis/ovaries and pelvic organs via the hypogastric nerve. Hence, electrical stimulation of this nerve is not organspecific and clearly activates numerous visceral afferents. Woodworth and Sherrington [490] first demonstrated that stimulation of the greater splanchnic nerves produced pseudoaffective responses consisting of viscerorn~tor responses and vocalization. Subs'e2iuent researchers have verified these findings by demonstrating that electrical stimulation of the greater splanchnic nerves [4,8,32~34,37,77,125,144,146,433] and branches of the splanchnics such as the celiac nerves [316], gastric nerves [317], hepatic nerves [3"._7], pancreoduodenal nerves [7], mesenteric nerves [228, 316-31[~,388], splenic nerves [105,317], renal nerves [1,74,260,370], testicular nerves [320] and ovarian nerves [257] will produce nictitating mere[ r a n e /
pupillary responses [4,37], visceromotor responses [8,33,34,77,105,125,144,146,316-318], alterations in respiration [4,7,34,125,257,320,388] and cardiovascular responses [1,4,74,105,125,146,228,257, 260,320,370]. By making lesions in the spinal cord and using pseudoaffective responses to electrical stimulation of the greater splanchnic nerve as a guide, Woodworth and Sherrington [490] and Davis [125] demonstrated that the spinal pathways for the production of pseudoaffective responses projected bilaterally, but predominantly in the anterior/lateral columns of the contralateral side. Davis further stressed the importance of short relays within the spinal cord since the only way to abolish the cardiovascular responses to nerve s~.imulation was complete spinal cord transection. Downman [144] reported that afferents traveling in the greater splanchnic nerve entered the spinal cord and ascended at least 4 segments. Johansson and Langston [228] characterized cardiovascular responses to nerve stimulation and determined that stimulation of high (electrical) threshold afferems in mesenteric nerves produced pressor responses; depressor responses were noted at lesser intensities of stimulation. These investigators also noted that high intensity stimulation of the mesenteric nerves produced a reflex vasoconstriction in kidneys and decreased mesenteric and skeletal muscle blood flows. Studies by Bardos and associates [39,40] examined behavioral responses to electrical stimulation of the stomach or small intestine (mucosal electrodes). They found that rats were able to discriminate the presence or absence of stimulation u~ing an operant behavioral paradigm and exhibited behavioral reactions that were consistent with the interpretation that electrical stimulation was aversive. Earlier, Cannon [77] examined the effects of greater splanchnic nerve stimulation in unanesthetized cats and observed visceromotor responses and vocalization, suggesting that electrical stimulation was noxious in character. Cannon also stimulated the lumbar sympathetic chain and got similar responses, but observed no behavioral responses with stimulation of the vagus nerve below the level of the recurrent laryngeal nerve or 6.:f ~ e sympathetic chain above the superior cerv:,caJ ganglion.
180
Neuronal indices. Numerous investigators have recorded from neurons responsive to electrical stimulation of abdo~vdnal visceral afferents that have cell bodies located in the spinai cord or supraspinal structures such as the thalamus [5,82,303,499,500], hypothalamus [5], cerebral cortex [12,13,116,143,352,459], cerebellum [353355,378,406,407,486] or medullary structures [e.g., 379,380]. Pomeranz et al. [385] demonstrated that spinal cord neurons in the deep laminae (presumably lamina V) of the thoracic spinal cord responded to both splanclmic nerve stimulation and natural cutaneous stimuli. Although visceral nerves also contain relatively large myelinated fibers with pacinian corpuscles for endings, these investigators were unable to identify any spinal neurons that responded to intensities of splanclmic nerve stimulation sufficient to activate only these fibers. The neurons studied had relatively large cutaneous receptive fields in comparison with neurons receiving only somatic input and responded, in general, to both noxious and non-noxious cutaneous stimuli. Gokin and associates [187,188] extended these findings to include viscerosomatic neuruas in the superficial dorsal horn and ventral horn of the thoracic spinal cord of the cat; others examined the cutaneous receptive fields of the spinal neurons quantitatively [96,98] and also have demonstrated the existence of long ascending projectior, s of visceroceptive spinal neurons to the brain [88,98,170,199,409]. Although a s,abset of visceroceptive spinal neurons with long ascending projections reaches the thalamus, the precise sites of termination of all visceroceptive neurons with long ascending projections have never been quantitatively determined. However, work by Cervero [88] suggests that most spinal neurons excited by electrical stimulation of the greater splanchnic nerve with long ascending projections to the brain have axons in the contralateral ventrolateral quadrant of the cervical spinal cord. Cervero also identified neurons with projections via the ipsilateral dorsolateral funiculus and others w~ih projections to the cervical spinal cord, but no visceroceptive spinal neurons have been identified as postsynaptic in the dorsal columns. Hence, spinal neurons receiving visceral inputs have patterns of distribution of projection similar to those
of somatic nociceptive spinal neurons. A more complete discussion of visceral inputs to specific sensory pathways is reviewed elsewhere [488]. Neurons excited by the electrical stimulation of the greater splanchnic nerves have been found in virtually every spinal segment. Akeyson enid Schramm [6] recorded from spinal neurons in the cervical spin~ cord of the rat that were responsive to electrical stimulation of the greater splanclmic nerve. Similarly, Hancock et al. [200] reported that neurons it~ the L6-L7 spinal segments of the cat also could be excited by electrical stimulation of the greater splanchnic nerve, even though afferents from this nerve enter the spinal cord roughly 10 spinal segments rostral [92,254]. Ammons and associates [21,24] also characterized neurons in the upper thoracic spinal cord that were excited by electrical stimulation of the greater splanchnic nerve. In 7 primate spinothalamic tract neurons with cell bodies in the T1-T5 spinal segments, they [21] demonstrated that a transection of the left sympathetic chain between the T5 and T6 ranti communicantes reduced the number of discharges to left splanchnic nerve stimulation by 27%. Sectioning of the sympathetic chain more caudally further reduced the neuronal response until, by the TS-T9 gap, 71% of the response to splanchnic nerve stimulation had been abolished. Additional lesions of the dorsolateral column of the spinal cord caudal to the recording sites had little additional effect on the neuronal responses, whereas lesions of the lateral and ventrolateral columns reduced or abolished the neuronal responses. In this way, it was determined that visceral afferent information traveled to the T1-T5 spinal segments by both extraspinal (sympathetic chain) and intraspinal routes, h~traspinal primary afferent pathways traditionally consist of Lissauer's tract and neighboring dorsal and lateral funiculi. However, the work of Ammons et al. [21] suggests that this is not the intraspinal pathway for visceral afferent information traversing four or more spinal segments. Other 'intraspinal' pathways conveying visceral afferent information have been demonstrated by Pavlasek and Duda [372] for descending excitatory inputs to lumbar spinal neurons from greater splanclmic nerve stimulation (propriospinal and spinobulbospinal pathways).
181
"!"aese pathways may have been the substrates for some of the ascending excitatory input to the upper thoracic spinal cord ,~ser~ed by Ammons et al. [21]. No matter wtv~t the precise routes for excitation are, it is apparent that the stimulation of a single visceral nerve, unlike stimulation of a somatic nerve, cma lead to the excitation of neurons in widespread segments of the spinal cord. In addition to the greater splanchnic nerves, other abdominal visceral nerves also have been electrically stimulated to identify visceroceptive spinal neurons. Seizer and Spencer [421,422] recorded from neurons in the middle to upper lumbar spinal cord segments excited by electrical stimulation of the sympathetic chain. Fields et al. [158] similarly demonstrated that sthnulation of the white rami communicantes of the sympathetic chain activated neurons in the upper lumbar spinal cord. Recently, Ammons in the cat and primate [14-17d] and Kneupfer et al. in the rat [245] electrically stimulated the renal nerves to activate spinal neurons, many of which had long ascending projections to the brain. Viscerovisceral and viscerosomatic convergence have been the rule rather than the exception in studies of spinal neurons excited by electrical stimulation of abdominal visceral and/or somatic afferents (Table II). For example, 100% of the neurons characterized by Ammons and Foreman [23,2,[' that responded to electrical stimulation of the !:~t splanclmic nerve also responded to electrical stimulation of thoracic visceral nerves. Only a few neurons described by Cervero [89], Ammons [15,23,24] and others [187,188,245] have had identifiable visceral inputs without identifiable convergent excitatery somatic receptive fields, some having no resl:onses to somatic stimuli whatsoever [89,187,18~,245]. Convergent cutaneous receptive fields were generally described as multidermatomal, centered in the dermatome corresponding to the spinal segment of study, and were significantly larger than the receptive fields of spinal neurons ~receiving only somatic input [9698]. The classification of visceroceptive neurons by their cutaneous receptive fields differs between laboratories, wtfi,ch suggests significant differences in species, preparation, technique and/or method of classification. This is of importance as the
classificatJ~'~ of ne onai types has bearing on the presumed function of these neurons. For example, t,:: ¢:~,nction of visceroceptive neurons that are of the class t type, responsive only to non-noxious cutaneous s~h'nuli, is questionably nociceptive. Ammons and Foreman [14-16,23,24] described neurons responsive to splanchnic nerve stimulation as predominantly class 3, responding only to noxious cutaneous stimuli; they found no class 1 neurons in their samples. In contrast, Cervero and associates [88,89,94-98,450,451] described neurons responsive to the same stimulus as predominantly class 2, responsive to both noxious and non-noxious cutaneous stimuli, but also characterized numerous class 1 and class 3 neurons that also were excited by visceral afferent stimulation. Given the importance of neuronal classification to assessing function of neurons, differences such as these make a precise formulation of the function of visceroceptive neurons difficult. Thoracic visceral nerves Reflex indices. Thoracic viscera include the
esophagus, heart, lungs, thymus and other lymphoid tissues, the diaphragm and the vessels and membranes surrounding these structures, including the pericardium and visceral pleura. The afferent nerve fibers from these organs to the spinal cord travel in the phrenic nerve and enter the upper cervical spinal segments, in the cardiac nerves that traverse the upper sympathetic chain, including the ~tellate ganglion, and enter the upper thoracic spinal segments, and in the thoracic splanchnic nerves (which are small branches of the thoracic ganglia of the sympathetic chain) and en*.er in multiple thoracic spinal segments. Since the heart is the most common source of clinically significant visceral pain from the thorax, numerous studies have electrically stimulated thoracic afferent visceral pathways such as the inferior cardiac nerve or the steUate ganglion and considered excitatory responses to be representative of cardiac or cardiopulmonary i~put, although afferents fr~rn other thoracic viscera may have been the source of excitation. Electrical stimulation of these afferents leads to significaL~t alterations in sympathetic efferent outflow, measured as cardiovascular changes [e.g., 248,381] or ch,~nges in sym-
Recording site
n
T2-4
T8-9
T8-9
T8-9
T8- i 1 T9-11 "1"9-11
T10-11 T11 T10-L2 Thoracic Thoracic T1-5
Cat
Cat
Cat
Cat
Cat Cat Cat
Cat Cat Cat Cat Primate Primate
T10-L1
T12-L2
TI2-L2
T12-L2
Rat
Cat
Cat
Cat
Renal nerve stimulation
T2-4
Cat
97-100%
?
61 64
100%
100%
84%
100% 100% 100% 100% 100% 100%
100% 1.00% 100%
100%
100%
96~
95%
98%
% ,u)nv. j
20
65
88
58 29 6 10 15 63
44 78 83
165
92
82
56
65
Greater splanchnic nerve stimulation
Species
VISCEROSOMATIC CON VERGENCE
TABLE II
excited excited (58) d grouped with inhibited (3) '~
[151
[161
[14l
0
0
0
0 0
13
12
10
10 0
33
4 3 11 29
0 2 2 0
0
0 4~ ?
0 3 ?
excited excited excited excited excited excited excited excited (83) d grouped with inhibited (5) excited inhibited
14 37 13 14 8
18 76 20 42 20
4 16 11 22 3
excited excited excited excited excited
44
36
10
36 4
8
0 5 2 34
3 11 ?
?
?
?
39 8 6 12 0 31 30
Class 3
excited
Class 2 7 1 1 5 1 4 42
Class I
Somatic classification b
0 0 0 0 0 0 7
excited inhibited excit./ir,hib. excited inhibited ? excit.ed
Response to stim.
[2451
[199] [170] [21]
[88] [951 [4091
[45o,451] [94]
[96]
1981
[86]
[89]
[231
[2q
[refl
3-inhibited 10-deep 5-deep 2-.'?
8-visc. only 50-.'? 9-deep 1-deep 5-inhibited
2-deep
lO-deep 33-7 6-?
3-inhibited 3-visc. only
1-inhibited 2-inhibited
Other
neurons neurons neurons neurons
SRT neurons; some excited by renal venous or ureteral occlusion
SRT neurons
STI" neurons
SIT STT SIT SIT
unilateral GSN input
bilateral GSN input
Some excited or inhibited by gallbladder dist. Some excited by gallbladder dist. Some excited by gallbladder dist. Lamina I neurons Deep laminae neurons
Comments c
T1-4
T2-4
T2-4
"1"2-4
T2-4
T2-4
T2-4
T2-4
Cat
Cat
Cat
Cat
Cat
Cat
Cat
Cat
135
64
40
58
72
101
64
61
92-9455
10055
9555
9755
96~
.9
95-10055
10055
100~g 97~$
[171]
[61]
[57]
[476]
[24]
[169]
[23]
[100]
[168] [456]
excited
excited
excited
excited inhibited excit/inhib. excit,~d
?
'~
excited
excited excited
14
5
3
1
15 1
8
10
27
5
99
33
39 8 6 53
68
51
34
,9 22
2g 33
?
TI-4 T1-3
Ca1 Cat
14
18
2;2
0
[17d]
18
44
46
32
100.~
[17c]
excited (62) d grouped with inhibited (6) excited
12
26
54
10055
[17b]
excited
11
T1 l - L 2
Primate
38
100~
[17a]
Thoracic visceral nerve stimulation (inferior cardiac or sympathetic chain) Cat T1-4 69 10055 [449] excited
Tll-L1
Primate
68
1005
40
T10-L3
Primate
66
excited
T12-L2
Cat
11-deep 8-inhibited 3-7
2-visc. only
2-inhibited
2-visc. only 22-.9 2-inhibited
3-inhibited
1-visc. only 1-7
2-deep
2-deep
8-deep
Some excited by bradykinin Some excited by PVCs or other cardiac mechanical stimuli STT and SRT neurons; some excited by bradykinin 4555 respond to CAO
Some respond to GSN stbn.
SRT neurons modulated by vagal stim. SRT neurons modulated by NRM stim. Also excited by gallbladder stim. SRT and STI" neurons
Cell bodies in laminae I, I!o Cell bodies in lawl.-~ae IV-VI
S'IT neurons; some excited by ureteral occlusion S I T neurons; some excited by renal pelvis distension
S T r neurons
Some excited by renal venous or ureteral occlusion
T2-6
C8-T5
C8-T5
Upper Thoracic T1-4
T1-5
T1-5
T2-4 T2-5
T2-5
T2-5
T2-5
T3-5
T3-5
Cat
Primate
Primate
Primate
Primate
Primate
7/anate Primate
Primate
Primate
Primate
Primate
Primate
axons + S1
T2-4
T8-9
Cat
Cat
Gallbladder atstension
Cat
Pelvic visceral nerves
Primate
Recording site
Species
TABLE II (continued)
28
26
110
31
30
41
42
58
9 38
45
85
42
31
69
41
84
100%
100%
50%
100%
100%
98%
98-100%
100%
100% I00%
100%
100%
I00%
100%
1(10%
100%
100%
% conv. a
excited
.9
excited
?
.9
excited excited
excited
excited
excited
excited
excited
excited
excited
Response to stim.
[86]
[23]
excited inhibited excited
[307,308] excited
[59]
[18]
[69]
[27]
[26]
[172] [25]
[21]
[20]
[22]
[68]
[19]
[60]
[99]
[req
7
0
0 0 ?
.9
0
?
5 1 .9
.9
8
7
25
17
2
1
9 14 8 4
? ?
29
35
0 2 2 0
0 .9
1
1
27
?
? 1
25
?
? 0
24
Class 2
0
Class 1
Somatic classification b
12 8 .9
.9
23
?
14
2
3
15 5 3 6
? ?
15
49
14
?
44
?
60
Class 3
1-?
m
1-inhibited
n
Other
35/40 with visceral mechanical fields had cutaneous input
Some SRT neurons; rome excited by bradykinin; total modulat, by PAGS STF neurons; some excited by bradykinin S'VF neurons modulated by vagal stim. STT neurons modulated by SC-PB stim. STT neurons modulated by N R M stim. S T r neurons; some excited by fallbladder stim. STT neurons; some excited by GSN stim. STT neurons Medial and lateral STF neurons; some excited by bradykinin Medial S I T neurons Lateral S I T neurons Med.-lat. tiFF neurons Medial STI" neurons inhibited by PVGS Lateral s T r neurons inhibited by PVGS Med.-lat. tiFF neurons inhibited by PVGS STF neurons, some inhibited by urinary bladder dist. STF neurons modulated by vagal stim. STI" neurons
Comments c
O0
T8-9 T1-5
C8-T5
S1-3
Lumbar
TI2-LI L7-$3
Cat
Rat
Primate
L6-S1 T12-L1
S1-3
Lumbar
T13-L2
L6-$2
Cat
Rat
Rat
Rat
107
177
33
30
8
? 17
19 17
20
72
12
42
30 17
49~
97~$
100%
83~$
100~$
50% 100%
100% 100~$
100~$
81~$
100%
100~$
100% 100~$
excited excited inhibited
excited (5) inhibited (7) excited inhibited excited inhibited excited
excited (27) inhibited (1) no response (14)
excited ?
inhibited
excited (7) inhibited (1) [215] excited inhibited [73] excited inhibited [343,345] excited excited inhibited [340] excited
[158]
[233] [319]
[319]
[73]
[215]
[158]
[58]
[sg] [20]
2
? ? 9 3 0 0 0 2 5 1
0 0 0
16 13 0 0 0 0
?
?
4 0
1
.9 ? 9 4 1 21 29 52 28 9
? 12 1
22 11 0 9 16 ll.
.9
?
13 12
1
? ? 1 0 0 1 19 33 0 31
? 4 0
1 0 0 1 3 2
?
?
7 5
2-proprio. 8-proprio. 4-visc. only 5-vise. only 46-vise. only 4-proprio. 12-visc. only
9-visc. only 2-proprio. 8-proprio. 4-deep
6-7 -
In medial spinal cord
In deep I~rainae
In superficial iam~ae
S I T neurons
S I T neurons
SIT. and SRT neurons
STl'neurons
? = not specified. a % cony. = percentage of neurons receiving excitato~ visceral input which also -~eive excitatory somatic input. b Somatic classification. Class I neurons are excited by non-noxious cutaneous shJ,~ufi. Class 2 neurons are excited by both noxious and non-noxious cutan,~us stimuli. Class 3 neurons are excited by noxious, but not non-noxious cutaneous stimufi. O~her includes the following: proprio, neurons excited by proprioeeptive inputs but aot cutaneous inputs; deep neurons excited by mechanical stimulation of ~abca~.~neous structures but not by cutaneous stimulation; inhibited neurons with no excitatory somatic input but inhibition of spontaneous activity by somatic stimuli; .rod vise. only neurons with no discernible somatic input. c Abbreviations: CAO, coronary artery occlusion, GSN, greater splanchnic nerve; NRM, nucleus raphe magnus; PAGS, periaqueductal gray stimulation; PVCs, premature ventric~,'~ contractions; PVGS, hypothalamic periventrieular gray stimulation; SC-PB, subce~leus-parabrachial region; SRT, spinoreticular tract; STF, spinothalamic tr~c~, stim., stimulation. o Number of neurons in total sample (n) responding as indicated.
Lumbar
Cat
Colon ~rectum distension
Rat Primate
Testicle compression
Lumbar
Cat
Urinary bladder distension
Cat and Primate
Coronary artery occlusion
Cat Primate
186
pathetic nerve activity [e.g., 471]. Electrical stimulation of thoracic visceral nerves also has been described as producing alterations in respiration and nictitating membrane responses [4,211]. In humans, thoracic visceral nerves, including the cardiopulmonary afferent pathways [Jonnesco, Leriche, cf., 273] and the phrenic nerve [141,494], have been stimulated to produce pain. Studies in which the phrenic nerve was stimulated are of particular interest since many were attempting to address basic questions related to the referral of visceral pain. Wollard et al. [494] electrically stimulated the phrenic nerve and produced immediate ipsilatera~ shoulder pain. These investigators then extensively infiltrated the shoulder with local anesthetic and were still able to produce pain localized t,~ the shoulder, although direct stimulation of the shoulder itself produced no pain. Doran and Ratcliffe [141] repeated these findings and further demonstrated that phrenic nerve stimulation could produce shoulder pain in a patient who had undergone a resection of the supraclavicular cutaneous nerves on one side and so was completely anesthetized across the shoulder. In other patients, they demonstrated that the intensity of phrenic nerve stimulation needed to produce shoulder pain was increased following infiltration of shoulder skin with local anesthetic, suggesting that visceral and tonic somatic inputs summate. Neuronal indices. Neurons responsive to electrical stimalati,~-,,f thora(:ic visceral nerves at intensities sufficient t o ~,cti~ate AS- ~ . d / ~ r C-fibers have been characterized in the upper thoracic spinal cord [18-27,57-61,168,169,171,172,449,456, 476], medulla [53-56] and thalamus [~,500]. The afferent pathways to and localization of spinal neurons excited by the electrical stimulation of thoracic visceral nerves has not been as extensively investigated as those of abdominal visceral nerves since studies have been limited to the upper thoracic spinal segments. As is the case for neurons excited by electrical stimulation of abdominal visceral nerves, viscerosomatic convergence is a common finding for neurons excited by electrical stimulation of thoracic visceral nerves. Exceptions are reports by Foreman and associates [57,169,456] of a small number of neurons apparently receiving only visceral in-
m
5ms
Fig. 6. Visceroceptive neurons - electrical stimuli. Example of a thoracic dorsal horn neuron in a cat excited by electrical stimulation. An oscillographic record of the response to electrical stimulation of the inferior cardiac aerve (stimulation artifact indicated by arrow) is shown; the ~nvergent cutaneous re~.eprive field of tb." neuron is illustrated below; the neuron was e×cited by fight touch and pinch [192a].
put. Catane(=s receptive fields of neurons receiving thoracic visceral input are relatively large, predominantly on the thorax and forelimbs, and centered in the dermatomes where recordings were made, primarily the upper thoracic spinal cord. An illustration typical of somatic convergence on a spinal dorsal horn neuron responsive to electrical sfimulation of the inferior cardiac nerve is presented in Fig. 6. Viscerovisceral convergence with input from the esophagus [180], gallbladder [20,23] and greater splanchnic nerve [20,21,23,24] also has been noted. Other studies [18-22,25-27, 58-61,169] have concentrated on spinothalamic tract neucons that respond to cardiac input since anterolateral chordotomies lead to partial relief from visceral pain [488] and the thalamus is unquestionably important to sensory processing. It should be noted, however, that anterolateral chordotomies also affect rostral projections to medulla, pons, midbrain and medial thalamus [487] and studies of spinal neurons projecting to these
187 supraspinal sites also are important for purposes of contrast and comparison [e.g., 58,61,169]. Pelvic visceral nerves Reflex indices. The two main pelvic visceral
nerves that have been stimulated electrically in studies of visceral sensation are the hypogastric and pelvic nerves. Afferents to the thoracic and upper lumbar spinal cord travel in the hypogastric nerve and afferent~ to the sacral spinal cord travel in the pelvic nerve, although recently a sympathetic 'contamination' of the pelvic nerve arising from the sacral sympathetic chain has been noted [219]. Stimulation of either of these nerves has been demonstrated to produce nictitating membrane responses [4], cardiovascular changes [4,418], alterations in respiration [4,176,418], visceromotor responses [176,317,498] and alterations kl sympathetic outflow measured directly from sympathetic preganglionic neurons [261,419]. Neuronal indices. Neurons excited by electrical stimulation of the hypogastric and/or pelvic nerves have been identified in the spinal cord [129,132,133,307,308], the po~i~ [] 77] and tha!amus [500]. Studies by Yokota et al. [reviewed in 500] of neurons in the shell region of the ventroposte:rolateral nucleus (VPL) of the thalamus deserve special notice; they compared the somatotopic representation of the convergent cutaneous inputs and the thalamic: location of neurons recei,~ing excitatory inpu~ from the hypogastnc, greater splanchnic and inferior cardiac nerves. Input from the inferior cardiac nerve converged on neurons located at the medial aspects of the shell region of VPL. Input from the hypogastric nerve was located in the lateral aspects of VPL and input from the greater splanchnic nerve was located between these two inputs, with many neurons excited by stimulation of the greater splanchnic nerve and also stimulation of one of the other two nerves. Convergent cutanecu~ receptive field~ of these thalamic neurons were similar to w~at is observed in the spinal cord: neurons with input from the inferior cardiac nerve typically had receptive fields in the upper limbs and thorax; neurons with input from the greater splanchnic nerve typically had thoracic and abdoram'~l receptive fields; and neurons with input from the hypogastric nerve typically had
lower abdominal and hind limb receptive fields. Similar convergence of cutaneous receptive fields with hypogastric or pelvic nerve input was noted by McMahon and Morfison [307,308] in spinal units that they considered to be local intemeurons in the sacral spinal cord and other units with ascending projections to the thoracic spinal cord or br~dn-stem. Modulation of responses to nerve stimulation
Studies on the modulation of responses to electrical stimulation of visceral nerves have been predominantly electrophysiological (e.g., individual neuronal responses were measured directly or grouped neuronal responses were measured as motor nerve evoked potentials or as alterations in the galvanic skin response, representative of increased sympathetic outflow). Sonoda et al. [433] demonstrated that potentials in the intercostal nerves evoked by greater splanchnic nerve stimulation (the viscerointercostal reflex) and a galvanic skin response in the forepaw of the cat to the same stimulus were both inhibited by electrical stimulation in the midbrain periaqueductal gray (PAG) and adjacent structures. Inhibition of the viscerointercostal reflex by stimulation in the PAG was abolished by bilateral lesions of the dorsolateral funiculus. The viscerointercostal reflex also was inhibited in a dose-dependent, naloxone-reversible fashion by the systemic administration of morphine (1-10 mg/kg). By utilizing graded stimulation of the greater splanchnic nerve, these investigators were able to demonstrate that both electrical stimulation in the PAG and morphine modulated the stimulus-response function relating the intensity of nerve stimulation to the amplitude of the viscerointercostal evoked potential in the same fashion. Fukuda and Koga [178] performed similar studies by stimulating rectal and vesical afferent nerves and found similar results. Spinal neurons excited by the electrical stimulation of visceral afferents have been demonstrated to be subject to tonic descending inhibition [88,94,95,450] or inhibition produced by the electrical or chemical activation of central nervous system sites thought to play a role in antinociceprive m~h~ufisms (e.g., the dorsolate:ral funiculus of the spinal cord [88], the nucleus raphe magnus and
188
adjacent regions in the ventromedial medulla [22,94,95,100,214,451], the periventricular gray of the hypothalamus [27], the PAG in the midbrain [99] a n d the subceruleus-parabrachial region of the dorsolateral pons [68]). In all of these studies, activation of the descending systems led to an inteasity-dependent inhibition of spontaneous unit activity (ff ~ny) a n d / o r unit act:.vity in response to visceral nerve stimulation. In these studies, Cfiber-related activity was relatively more inhibited than A-fiber-related activity wh.en tested, although this may be an artifact of the lower rate of C-fiber firing. Vagal nerve stimulation has also been demonstrated to produce an inhibition of spinal neurons excited by visceral nerv~ stimulation [1820,26,456], although some spinal neurons were noted to be excited by vagal nerve stimulation. Exceptions to descending inhibition have been noted by Cervero and associates [88,94,95,450,451] who characterized spinal neurons that were e x cited by descending influences. The application of a cold block to the cervical or upper thoracic spinal cord led to the attenuation or abolition of excitatory responses to stimulation of the greater splanclmic nerves, suggesting the existence of an excitatory spinobulbospinal loop. In a subgroup of these same neurons, electrical stimulation in the ventromedial medulla produced excitatory responses followed by a period of inhibition [94,95,4:il]; injections of the excitatory substance DL-homocysteic acid into these same brain-stem sites only produced inhibition, tlence, fibers of passage in the ventromedial medulla arising from an unknown location were likely responsible for the descending excitation [451]. These fibers may likely be components of the spinobulbospinal mechanisms of excitation noted previously by Pavlasek and Duda [372]. Segmental inhibitory effects due to repeated electrical stimulation of either the visceral nerve itself or same segmental somatic nerves also have been noted to modify neuronal responses to visceral nerve stimulation [385,421,422,451]. That is, following initial stimulation of the splanchnic nerve or conditioning stimulation of a somatic nerve, spinal unit responses to stimulation of the splanchnic nerve were reduced in magnitude for 150 msec-1 sec. Seizer and Spencer [422] pre-
sented evidence that the mechanism for this phenomenon is primary afferent depolarization. In general, it is apparent that neurons excited by the electrical stimulation of visceral nerves appear to be subject to the same segmental and suprasegmental modulatory influences as nociceptive neurons excited by the electrical stimulation of somatic nerves. Since most of the neurons examined in the above studies had both vis~ral and somatic inputs, this should not be suprising. To the best of our knowledge, no studies have attempted to examine the effects of analgesic drugs (e.g., morphine) on spinal neurons excited by the electrical stimulation of visceral nerves. S u m m a r y - electrical stimulation
Electrical stimulation of visceral nerves is a reliable reproducible stimulus, the intensity and duration of which can be easily controlled. Electrical stimulation of abdominal visceral nerves and organs has been demonstrated to produce reports of pain in humans and vigorous pseudoaffective responses in animals. Electrical stimulation of the mucosa of the gut also has been demonstrated to alter behavior is rats, suggesting the aversive nature of the stimulus. Numerous spinal neurons have been characterized that are excited by electrical stimulation of visceral nerves and, in general, many would be classified as nociceptive based on their convergent cutaneous receptive fields. Some excitatory responses to the electrical stimulation of visceral nerves have been demonstrated to be inhibited by presumably antinociceptive manipulations. The biggest drawback to the use of electrical stimulation of visceral nerves is that it is neither a natural stimulus nor is it modality- or organspecific. Further, alterations in the characteristics of primary afferents within the viscera due to pathological processes, which appear clinically to be important to an understanding of visceral pain, are not amenable to study using only electrical stimulation as a stimulus. M~c~a~ical stimuli as noxio~ visceral stimuli
As reviewed by Lewis [273], mechanical stimuli such as traction of the mesentery, distension of
189
hollow organs, stretch of serosal tissues and compression of some organs such as the testes produce pain in humans. These are stimuli which also produce pain in pathological states such as obstruction of the common bile duct or gut. Lewis also noted that distension of hollow organs such as the gut was most painful when long continuous segments of gut were simultaneously distended. High pressures within small segments were not as efficacious in producing pain. As discussed by Lewis [273], numerous clinicians such as Lennander, Bier, Capps, MacKee~e and Wilms have noted the relative ineffectiveness of pressure, cutting, scratching or pinching of either healthy or inflamed visceral structures for the production of pain in humans. The parietal pleura and peritoneum covering the inner surfaces of the chest and abdominal walls are well accepted as being sensitive to tension as is adjacent mesentery, but the visceral pleura, peritoneum and visceral parenchyma are often insensitive to probing. Pain often is elicited using these same stimuli when the viscera are inflamed. An example is a case report by Wolf [cf., 203] of a patient with a gastrostomy in whom the mucosa of the stomach could be observed and manipulated directly. When the gastric, mucosa of this patient became hyperemic and engorged, the ~hreshold for pain was reduced to the point that pressure or pinching of the mucosa became profoundly painful whereas at other times, when the muco~a appeared normal., these stimuli were not painful at all. Similarly, Kinsella [241] demonstrated ~.hat pressure applied to an isolated inflamed appendix readily produced pain. Because distension of hollow organs is a natural stimulus which produces pain in humans, numerous studies have examined sensations evoked by mechanical stimulation of hollow organs. These include the gastrointestinal tract, the urinary tract, the vagina/uterus and the biliary tree/gallbladder following surgical manipulations. As the gastrointestinal tract is easily reached via natural orifices, experimental investigations of the gut outnumber those performed in all other viscera combined and will be considered in some detail. Hence, to facilitate reading, the studies of visceral nociception involving the gut
are listed under the subheadings of human studies, reflex and behavioral studies, neuronal studies and studies of modulation. Discussions of other organ groups will not be similarly subdivided, but the same format will be followed. Gastrointestinal gract Human studies. Since the time of Hertz [209],
numerous clinical studies in humans have distended the gut to produce pain. Two early investigators, Payne and Poulton [373], began their study of visceral pain by examining patients with intermittent pain of presumed gastrointestinal origin. Using motility-monitoring balloons, they demonstrated that specific movements of the esophagus, stomach, duodenum and jejunum were associated with patient reports of pain [see also, 213]. Payne and Poulton [374,375] then repeated studies by Hertz [209] and artificially distended their own esophaguses, correlating sensation with the volume/pressure of distension. They described their pain as 'continuous and burning' at low volumes/pressures and 'gripping' at the greatest volumes/pressures of distension. Pain was referred from the area of the suprasternal notch to the xiphoid process and sometimes to the costal angle, with radiation through to the angle of the left scapula. Pain was experienced with spontaneous conh-actions of the esophagus on non-compressible balloons and with the maintenance of a minimal constant pressure within a distending balloon (constant volume distension produced contractions and pressure waves witlfin the balloon; pain was correlated not with peak pressures within the balloon, but with the maintenance of a minimal 'diastolic' pressure of 30 cm water). Painful distensions produced alterations in the patte .,'n of breathing and, if the experimental protocol wa~ prolonged, the experimenters began to experience cutaneous hyperesthesia in the skin over the sternum. Polland and Bloomfield [384] confirmed the findings of Payne and Poulton by distending the esophaguses of 39 volunteers. A quote from their stu0y is illuminating; 'The most striking feature of the referred sensations was the inability of the patient as a rule tc, Cescribe them exactly. On the whole, they seemed o fall under the heading of
190
p a i n . . . l t was difficult to define the referred sensations in relation to body surface and while the subjects pointed to a fairly definite location in front or in back, the pain was usually described as being inside rather than superficial.' Descriptors of the pain included 'burning,' 'a severe dull ache,' 'something sharp,' 'a kind of suffocating pain, like one wanted to take a breath and couldn't' and 'a pressure, no pain, but it hurts.' In addition to pain referred to midsternal and epigastric regions, pain was also 'localized' over the entire anterior chest wall, in the back and occasionally in the neck or face. These investigators also examined volume distension of the stomach, duodenum and colon [63]. Descriptors of the pain originating from the stomach were similar to those ~sted above, but the pain was localized primarily in the epigastric and periumbilical regions. The ~olume threshold for pain sensation varied markedly front 400 to 1500 ml. Inflation of a balloon in the duodenum produced a more intense pain and sites of referral were predominantly epigastric and periumbilical. Duodenal pain was likened to esophageal pain, but was less like stomach pain in patients tested i,l all sites. Distension of the descending and sigmoid colon produced diffuse abdominal pain to left sided pain described as 'ccamps,' 'like gas pain' and ':~r~'ssurc pain.' An interesting study by Weiss and Davis [477] also used balloon distension of the esophagus as a stimulus. These investigators infiltrated the skin with local anesthetic over sites of referred pain from balloon distension and reported that the referred pain shifted from the original site to an adjacent site, only to return to the original site foUowing cessation of the local anesthesia. These investigators repor~.ed that pain was never abolished by the local anesthetic, but that the imensity was reduced and localization of the pain was affected. Chapman and Jones [102] were the first to determine pressure thresholds for painful sensations utilizing balloon distension of the esophagus in 29 volunteers. These investigators sl,~wly increased the pressure within the distending balloon until volunteers reported a ~ensation of substernal fullness and continued until the volunteers reported that the sensation had become painful, described as ,~. sense of 'oppression,' 'heartburn,'
'a cramp ache' or 'a sharp stab.' Thresholds for the sensation of substernal fullness varied from 15 to 90 cm water (most < 35 cm water) and were highly correlated with cutaneous thermal pain thresholds in the same volunteers. However, volunteers were unable to define a precise pressure when the substernal fullness acquired a definite hurting quality as the sensations were a continuum. These investigators were concerned that tonicity of the esophageal wall affected their pressure thresholds and administered atropine sulfate to 4 individuals. Atropine produced a 307o reduction in the resting tone of the esophagus (increased volume of distension), but did not change the visceral sensory pressure threshold. Moving down the alimentary tract, Bentley and Smithwick [48] distended the jejunum of 6 healthy individuals, 3 of which subsequently underwent partial sympathecto~es for hypertension. Pain due to jejunal distension was described as 'like intestinal colic but more severe and nauseating than any colic vet experienced,' 'sickening' and like a "stomach ache.' Pain was roughly localized co the epigastric region at low volumes of distension ai:d spread to include the entire upper abdomen at greater volumes of distension. After partial sympathectomies/sglanchnic nerve division, pain was either abolished or iateralized to one side whereas previously it had been a midline sensation. Similar studies and results were reported by Ray and Neill [391]. Goligher and Hughes [189] examined the sensibility of the sigmoid colon and rectum using volume distension with pressure measurements. A notable finding was that the sensation of pain was related to the pressure within the balloon rather than the volume; rapid balloon inflation with a fixed volume of air produced pain which waned as the intestinal wall relaxed and the intraluminal pressure lessened. Descriptors of the evoked sensations varied from 'definite pain like a colic but continuous' to the sensation of pressure. Goligher and Hughes made a distinction between colonic sensation and rectal sensation, the former being 'pain' carried by afferents in the sympathetic nerves and the latter 'fullness' carried by afferents in the pelvic nerve. However, they were unable to localize this pain specifically to the colon or rectum.
191
Lipkin and Sleisinger [278] were the first investigators to use controlled, constant pressure stimuli in studies of sensation from ~he gut. Using balloons to distend the esophagus, ileum or colon phasically in 51 patients, they demonstrated that the latency from the onset of the phasic stimulus to patient reports of pain was directly related to the intensity of the distending stimulas. At distending pressure~ ~,reater than 50-60 mm Hg, reports Gf pain were immediate in all 3 organ sites and pain was the only sensation. Sites of referred pain and descriptors of this pain were similar to those described above. At lesser distending pressures, the stimulus was not reported as painful for up to I min following the onset of distension and was preceded by a sensation of pressure over a large abdominal or thoracic area. This pain was
described as an aching pain which arose within a smaller area of the total area to which the preceding pressure sensation had been referred. The minimal intraluminal pressure to produce painful sensations from the esophagus was 39-47 mm Hg, from the ileum 44-59 mm Hg and from the colon 40-50 mm Hg. It should be noted that the reported values of distending pressure were 'corrected' values which the investigators calculated from measured values by subtracting the pressure necessary to overcome the elasticity of the distending balloon. Measurements made in the same patients on 3 different days established that responses of these p_a.tie~ts to the same distending stimulus (sigmoid colon, 74 mm Hg) were reproducible and reliable. Using this same stimulus, these investigators also documented that the re-
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Fig. 7. Psychophysiological experiments. Balloon distension of a 25 cm segment of sigmoid colon (60 nun Hg, 30 sec, constant pressure control) led to achy pair= localized to the lower abdomen, perineum and upper lumbar back. The area illustrated on the cartoon indicates where pressure ~:as sensed during distension; the completely filled area indicates where both pain and pressure were sensed. Colonic distension led to an increase in blood pressure (right - top) and a decrease in heart rate (right - middle). Subjectively, the intensity of unpleasant sensations increased during sustained distension (right - bottom). [Ness, Metcalf and Gebhalt, unpublisi~ed.]
i92
sponses of patients to this consistent stimulus fc,Uowed a norm~ distribution. Other studies [41,46,79,101,149,155,230,236, 240,251,262,263,299,32%332,395,397-399,446,484] have verified findings of these investigators and have consistently demonstrated that pain produced by distension of the gut is very similar, if not identical, in intensity, quality and location to pathologically experienced pain arising from the gut. An illustration representative of this literature is given in Fig. 7. These studies, in the aggregate, suggest that alterations in sensation (e.g., visceral hyperalgesia) may be a pathological condition which r e s ~ s in abnormal gut function or that local pathological conditions produce abnormal gut h~.nction which leads to an increase in pain. Most of these studies used volume distension as a srmulus, w~ch fails to differentiate pathological changes in compliance from hyperresponsivity or hypersensitivity of the bowel, and hence at present no conciusive statement can be made regarding hyperalgesia of the gut. In summary, human psychophysiological experiments related to pain produced by distension of the gastrointestinal tract reveal that pain is produced when the intraluminal pressure of this hollow org~,r~ is maintained above a certain pressure threshold. Pressure thresholds Are ~:'eliable measures of pain thresholds within individuals (~epeated measures) ~nd between different indivi,tua!s (threshold pressures are normally distributed), whereas volumes of distension necessary to evoke reports of p~in were neither reliable within the same subject nor between subjects. The descriptors of experimental pain evoked from the gut were similar to the descriptors of pathological pain, but varied widely. Initial sensationn to low volumes/pressures of distension were described as non-pai~ful pressure which became painful as the intraluminal pressure increased or the stirnuius was maintained. Studies ha humans did not report whether sensations or thresholds changed with repeated distensions nor did they report wheiher any physiological changes (e.g., cardiovasc~flar responses) consistently occurred in response to distension. Reflex and behavioral studies. Mechanical stimulation (disten:;ion oa ce~apression) of the gut
also has been used widely in non-human animal investigations of visceral nociception. In the eat, rat, rabbit and dog, mechanical stimulation of the esophagus [206,415], stomach [146,151,206,283, 284,302,310,317,387,420]~ small intestine [34, 104,111,112,117,146,147,191a,206,231,269,274,310, 317,388,420,467] and large intestine/rectum [115, 123,175,206,227,285,342,454,470] have been demonstrated to produce nictitating membrane/pupillary responses [147,206,310,470] cardiovascula~ responses [104,123,146,147,151,175,231,269,274, 283,284,302,342,387,415,454,470], changes in respiration [34,117,175,I91a,388,415,420] and visceromotor responses consisting of the contraction of abdominal a n d / o r hind limb muscles [34,111, 112,115,123,146,147,175,227,274,288,317,342,467]. Stimulus-response functions relating thz intensity of the distending pressure and the magmtude of cardiovascular changes have been noted [151,284,302,342,470]. Both the magui'ude and qu.,dity of the cardiovascular changes reported differ among preparations, species and investigators, some reporting increases in blood pressure/heart rate, others reporting decreases. We [342] investigated the influence of anesthesia/preparation on cardiovascular responses to coloreetal distension in rats arid found that the response to colorectal distension in unanesthetized intact rats was a brisk presser response with tachycardia while in deeply anesthetized, acutely prepared, rats it was a depressor response with bradycardia (Fig. 8). Whether the differences in responses to distension were due to direct effects of the anesthetics or secondarily to physiological alterations such as depth of respiration is unknown. Regardless, such data clearly indicate that the preparation can significantly influence the responses measured in the rat and likely other species as well. Pseudoaffective responses to distension of the gut are blocked by splemchnectomy [e.g., 283] and selective rhizotomy at various thoracic and uppe~ lumbar segments [206,310], except for responses to distension of the 6esccnding colon and/or rectum [206]. In the cat, visceromotor and cardiovascular responses to distension of the gut could be elicited ir decerebrate preparations [e.g., 146] and in spinalized preparations by some investigators [e.g., 14619 but not by others [e.g., 274]. In the rat,
193 mmHg
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markedly reduced blood flows when mtraluminal pressures approach intensities that would produce pare m immams. The iochca~ic ~:hanges produced secondary to this reduced blood flow potentially could be responsible for pain originating from the gut or could be a sensitizing factor responsible for the initial increases in magnitude of neuronal, cardiovascular and visceromotor responses to
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cardiovascular and visceromotor responses to colorectal distension are vigorous in the decerebrate state, but th,: visceromotor response is apparently abolished and the cardiovascular responses markedly attenuated by spinal transection [342]. Using pseudoaffective responses as a measure of afferent input:, Downman et al. [147] were able to produce responses with selective compression of the mucosa, the musculans and the serosa of the small intestine, implicating all 3 sites as sources of pain due to distension. Other studies have examined the effects of distension on blood flow in the gut [65,201,202,360] and have o~served
Fig. 9. Behavior. Examples of alterations in behavior produced by a s4sceral stimulus. Using a conditioned avoidance paradigm in which rats were placed on a 15 x 15 x 10 cm platform in an open field mad the latency to step down from the platform measured, rats (n = 5/group) received colorectal distension (CRD, 20-80 mm Hg, 20 sec) when both forepaws were placed on the floor whereas control rats; (n = 10) did not. When intrahinunal pressures of CRD were 40 or 80 nun Hg, all rats avoided CRD by remaining oil the platform until cutoff (120 sec). At intraluminal pressures of 30 mm Hg or less, experimental rats did not behave diffe:~:ntly than control rats. Data are expressed as the mean step-down latency (A) and percentage of rats reaching criterion (B; criterion--stepdov, a latency > 120 sec for 2 consecutive trials). Note: lines have been separated slightly for clarity [Ness, Gebhart and Randich, unpublished; see 342].
194
colorectal distension observed in the rabbit [227] and rat [342,343]. One study has examined whetL¢r distension of the gut is aversive to animals [342]. Using a conditioned avoidance paradigm, colorectal distension was shown to alter/inhibit the normal step-down behavior of rats when placed on a raised platform in an open field at. an intraluminal pressure threshold for effect near 30 mm Hg (Fig. 9). Neuronal studies. Distension of the colon/ rectum has been used ,ts a visceral stimulus in studies of spinal dorsal horn neurons in cats [133,154,160,215,307,308] and rats [73,340,341, 343-346]. Fields et al. [159,160] recorded from axons traveling in the white matter of the cat spinal cord, predominantly the ventrolateral quadrant, and characterized these units as excited or inhibited in response to distension of the gut, gallbladder a n d / o r urinary bladder. They reported a b~-gh degree of viscerosomatic convergence in ascending fibers (presumably projection neurons) and descending fibers (presumably proprio~pinal or bulbospinal neurons); all neurons 'responsive' to distension (excitatory or inhibitory responses not specified) also responded to a somatic stimulus. Likewise, they noted a high degree of viscerovisceral convergence. DeGroat et al. [133] c~'aracterized sacral spinal interneurons near the parasympathetic motor nucleus and found a reciprocal relation between activity produced by urinary bladder and colonic/rectal stimulation: of 25 neurons excited by rectal stimulation, 13 were inhibited and 2 were excited by bladder distension while of 26 neurons inhibited by rectal stimulation, 17 were excited and 3 were inhibited by bladder distension. Convergence of excitatory input from the vagina and perianal region was also noted. McMahon and Morrison [307,308] no~ed somatovisceral and viscerovisceral co,vergence in recordings from 26 spinal units excited by mechanical probing or distension of the colon/ rectum in the cat; 7 of these neurons also were excited by urinary bladder distension and 6 were inhibited by the same ~tir,~ulus. Nine of the neurons excited by distension of the colon/rectum had long ascending projections to the C1 spinal segment and also encoded the intensity (pressure) of coiomc distension in a monotonic accelerating fashion.
We [340,341,34.a-346] have characterized similar neurons in the rat by quantifying the responses of > 300 neurons located in the T13-L2 and L6-$2 spinal segments to phasic pressure-controlled balloon distension of the descending colon and rectum. Based on the temporal relation between neuronal responses and the phasic distending stimulus (80 mm Hg, 20 see), 4 groups of neurons were identified. Mo~t units (73~) were excited coincident with the onset of the distending stimulus; the responses of approximately one-third of the neurons abruptly terminated coincident with termination of the distending stimulus ('abrupt' neurons) while responses in another one-third of the unit sample were sustained for 4-240 sec following termination of the distending stimulus ('sustained' neurons). The spontaneous activity of approximately one-fifth of the unit sample was inhibited by the distending stimulus and the remaining units exhibited relatively long latencies ( > 4 sec) from the onset of the distending stimulus until an excitatory response occurred. Pressure thresholds for responses extrapolated to near 0 mm Hg for 'abrupt' units and 15-20 mm Hg for 'sustained' neurons (Fig. 10). Units of all grot~ps except those with long latencies for resl:,onse were found to have long ascending projections to the brain localized to the ventrolateral quadrants. Both abrupt and sustained neurons were excited by intraarterial (abdominal aorta) administration of bradykinin, were under tonic descending inhibition and had a high degree of somatovisceral convergence with relatively large cutaneous receptive fields. Honda [215] recorded from 23 neurons located near the central canal of the sacral spinal .cord of the cat that were excited by colonic distension. Somatovisceral con~'~rg~ce (cutaneous receptive fields in the perineal region and hind limbs) was documented for 83~ of these neur~,~:s. Viscerovisceral convergence with excitatory input from the bladder was noted in 16 of the 23 neurons. Honda also labeled several of these neurons intracellularly, demonstrating patterns of dendritic arborization ranging from restriction to the area near the central canal to extension through laminae V and VII into the entire base of the dorsal horn. No distinct cell morphology was apparent for neurons excited by colonic distension. However,
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these neurons were simply classified and so the functional classifications may have been too broad to allow for definiti, on of a pattern. Recent work by Garrison et at. [180,181] has revealed the existen~ of neurons in the thoracic spinal cord encoding distension of the distal esophagus. These neurons were found to encode volume distension in a monotonic accelerating fashion. Distension of the gut also has been demonstrated to affect higher-order neurons in the medulla [e.g., 379], ports [151,1"/7], thalamus [82,85], hypothalamus [e.g., 226] and cortex [e.g., 85,116]. Of these reports, that by Carstens and Yokc~ta [82] is particularly interesting. They recorde~ from units located at the junction of thc
midbrain and posterior thalamus and tested for responses to distension of a fistulated portion of the jejunum. Of 134 units excited by splanchnic nerve stimulation, 28 also were excited by distension of the jejunum. Nine of these 28 units responded o ~ y at the onset of distension and 7 had convergent cutaneous receptive fields that responded to low threshold mechanical stimuli; 5 of the receptive fields were relatively small, consisting of 1 limb or less. The other 19 units gave responses which lasted through all or most of the period of distension, 6 outlasting the stimulus. All 19 of these units had large receptive fields, consisting of 2 or more limbs and often the entire body, and 9 of these responded best to stimuli such as pinch or noxious heathlg of the skin. Although not
~96
quantified, the responses of these 19 units appeared to be graded in response to graded distension. Elam et al. [151] also have demonstrated graded responses of locus ceruleus neurons directly related to the magnitude of d~tension of the distal colon and stomach. Modulation. Two studies in humans have attempted to modulate responses to experimental distension of the gut. In one of these, Woolf et al. [492] inflated a duodenal balloon and demonstrated that the parenteral administration of morphine sulfate led to an increase in pain threshold and pain relief. Payne and Poulton [375] reduced the subjective sensation of pain due to distension of an esophageal balloon by utilizing a amstard pack applied to the anterior chest wall, thereby producing 'counter-irritation' - - the masking of one pain by another. Several investigators have utilized pseudoaffective responses to distension of the gut for pharmacological studies of visceral pain, some in anesthetized animals, others in unanesthetized physiologically intact animals. Lembeck and Skofitsch [269] and Clark and Smith [104] reported that depressor responses to distension of the proximal jejunum in deeply anesthetized (pentobarbitai, urethane) rats were inhibited by opioids and by neonatal pretreatmcnt, with capsaicin. Unfortunately, unreliable responses to distension app~wently limited the use of this model of visceral pain: only 60% of the rats had depressor responses in one study [269] and 72% in the other [104] and repeated measures in the same rat led to a reduced response [269]. Similar depressor responses tv dis:c~ :sion of the colon and rectum of deeply anes~nctized rats have been noted [342] (Fig. 8). In awake, unanesthetized rats, MacKenzie-Taylor et al. [288] reported that systemically administered opioids increased the volume of coIonic distension needed to evoke a visceromotor response with a selectivity of opioid receptor subtypes. Coombs and associates [111,112,113a], utihzmg a volume-distended duodenal balloon to evoke a visceromotor response (writhing) in rats, re:poll
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opioids and the analgetic c~2-adrenoceptor e~gop.ist clonidine produce dose-dependent inhibition of this response. Unique to this model, chronic surgi-
cal implantation of the balloon prodm.c., local (duodenal) inflammation [111]. Reflex responses to pressure-controlled colorectal distension in rats have been demonstrated to be reliable and reproducible both between and within animals and are dose-dependently inhibited by opioids given intravenously [342] or intrathecally [342], by intrathecal a2-adrenoceptor agonists [123,342], by electrical stimulation in the PAG of the midbrain or rostal ventromedial medulla [Ness and Gebhart, unpublished] and by presentation of conditioning noxious stimuli in distant cutaneou3 receptive fields [344], which may be related to the counterirritatior~ of visceral pain in humans noted above [375]. Examples of the modulation of responses to colorectal distension in the rat are given in Fig. 11. Recent work by Jensen et ai. [227] demonstrates similar reproducibility and reliability of the visceromotor responses to pressure-controlled coionic distension in rabbits and inhibition of the responses by morphine. Modulation of neuronal responses to distension of the gut also have been examined. Morphine and clonidi,c produce dose-dependent, antagonist-reversible inhibition of spinal neurons excited by colorectal distension [346]. Electrical stimulation in the PAG or rostroventromedial medulla produces intensity-dependent inhibition of neurons excited by eolorectal distension, an effect also produced by chemical activation of cell bodies by glutamate in the same supraspinal sites [341]. Conditioning noxious stimuli applied to distant cutaneous receptive fields also modulates the activity of spinal neurons excited by colorectal distension [344].
Urinary bladder There is limited e.xperimental information about pain originating from the urinary bladder, but a wealth of clinicai data. Cystic calculi or rapid filling of the urinary bladder during cystoscopy commonly produces pain that is poorly localized to the lower back, suprapubic and perincal regions. This pain has been studied clinically during cystometrograms where a volume of fluid is infused via a catheter into th,: bladder; intravesical volumes, intravesical pressures and subjective sensations are recorded. Typically, the cystometro-
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Fig. 11. Modulation of visceroeeptive neurons. A: data from 3 thoracolumbar spinal dorsal horn neurons in the rat excited by coloreetal distension (CRD; 80 mm Hg, 20 see). The control neuron gave consistent responses during CRD (repeated every 4 min) for a period of 2 h, whereas application of a 25% solution of turpentine solution to the colorectal mucosa (at arrow) led to increased responses in another neuron. In a third neuron, the intravenous administration of morphine sulfate (mor) led to a dose-dependent naloxone (nal)-reversible inhibition of responses during CRD. B: stimulus-response funetimts (SRFs) of the same units in A, characterizing neuronal responses (total no. impulses minus spontaneous activity) t,., graded stimuli. Responses at all intensities of CRD were enhanced following turpentine treatment (top) while responses of the control unit were the same at the begim',h-,g ~a,d end of the experiment (center). Morphine (bottom) attenuated responses during CRD. Filled symbols are SRFs at time 'zero'; open symbols are SRFs at times indicated by * ha A [346a].
gram has been employed to study compliance or spasticity of the bladder and not sensatio~lo Precise, controlled stimuli typically have not been used in studies of human urinary bladder sensation. A continuum of sensation during distension of the bladder has been reported; the initial sensation of ful~xless becomes compounded by a sense of urgency and urethral sensations until frank pain with profound urgency is finally expe-
rienced [134,33~]. Reports of pain appear to be directly related to the pressure of the fluid within the bladder and not to the volume (although volurae is obviously related to pressure L'~ a c!osed viscus), since pain waxes and wanes with isovolumetric, contractions of the bladder. Simple sympatheetomy does not abolish urinary bladder sensation, but sympathectomy in addition to rhizotomy at $2-4 or pelvic nerve section does
198
lead to a loss of sensation produced by distension of the bladder [267]. Anterolateral chordotomies abolish both the sensation of the need to micturate and pain from :he bladder during distension [338]. Distension of the bladder in humans often has been noted to produce cardiovascular and other autonomic responses [120,193,495]. Most animal studies utilizing mechanical stimulation of the urinary bladder, predominantly distension, have been concerned with micturition reflexes or interactions with other autonomic functions, such as defecation reflexes [e.g., 133,304]. However, some studies do contain information related to pseudoaffective responses and responses of neurons which couid potentially be nociceptive. Distension of the bladder produces cardiovascular changes in both intact and spinalized animals [151;333,419,426,452-454,470,472], changes in respiration [154,175,314,333,4!8], visceromotor responses [154,175,314], responses of the nictitating membrane [470], and cha'ages in circulating catecholamines and cortisol [426]. The cardiovascular responses to distension of the bladder were directly related to the pressure within the bladder and only indirectly related to volumes of distension. Infusion of the local anesthetic procaine into the lumen of the urinary bladder blocked cardiovascular responses to distension [472], as did complete splanchnectomy [333]; cardiovascular responses were attenuated by cutting either the hypogastric or pelvic nerves, but abolished only when both nerves were cut [453]. Numerous studies have examined the effects of opioids on the micturition reflex [e.g., 148], but to the best of our knowledge none have examined the effects of opioids on pseudoaffective responses to urinary bladder distension. Several studies have recorded from spinal [132,133,158,159,215,232,307,308,319] and pontine [e.g., 151,177] neurons responsive to distension of the urinary bladder. Spinal neurons excited by bladder distension were located throughout the dorsal horn, in the area near the central canal and in the region of the parasympathetic (sacral) and sympathetic (thoracic) nuclei; some of these neurons sent projections rostrally through the ventrolateral quadrants of the spinal cord. In addition to neurons excited by urinary bladder distension,
some spinal neurons are inhibited. In several studies, graded distension of the bladder produced graded increases or decreases in neuronal activity in apparent direct relation to the intraluminal pressure and only indirectly with the volume of distension [132,133,151,307,308,319]. Pressure thresholds for the excitation or inhibition of specific neuronal types has not been undertaken quantitatively. However, an interesting finding by DeGroat et at. [133], who examined sacral interneurons near the parasympathetic motor nucleus, was the existence of at least two populations of neurons excited by distension of the urinaqr bladder: one group encoded the intensity of pressure-controlled bladder distension in a hnear fashion both above and below the pressure threshold necessary to evoke micturition and a second population of neurons exhibited a near maximal firing rate when the micturition threshold had been exceeded. The responses of this second population of neurons were similar to responses of preganglionic parasympathetic neurons to the same stimulus [] 32]. One interpretation of these data would suggest that the latter group of neurons were exclusively involved in non-nociceptive autonomic reflexes whereas the former group of neurons, or a subset thereof, were likely involved in nociceptive processing. Honda [215] recorded from 48 neurons that were located near the central canal of the sacral spinal cord in the cat excited by distension of the urinary bladder. A high degree of somatovisceral convergence was noted (81%) with convergent cutaneous receptive fields in the perineum and hind limbs. Viscerovisceral convergence also was common; excitatory input from the distal colon was found in 13 of these neurons. Honda filled intracellularly several neurons receiving excitatory input from the urinary bladder. As noted above for cells labeled by Honda that responded to colonic distension, no unique cell morphology was apparent for neurons r~ceiving bladder input, although the characterization of the neurons was simple and the sample small so that patterns may yet become apparent. A consistent finding in studies of spinal neurons excited by urinary bladder distension is the existence of convergent cutaneous receptive fields
199
in a high percentage of the neurons tested. Milne et al. [319] found that of 36 primate spinothalamic tract neurons excited by distension of the urinary bladder, 100% of those neurons located at the thoracolumbar junction (n = 19) and 76% of those located in the sacral spinal cord (n--17) had convergent cutaneous receptive fields; the other 4 neurons located in the sacral cord had 'deep' (subcutaneous) convergent receptive fields. Other studies cited above of neurons excited by distension of the urinary bladder have not demonstrated a 100% convergence between visceral and somatic excitatory inputs, but have not examined spinothalamic tract neurons specifically. Inhibitory cutaneous receptive fields of spinal neurons included segmental non-noxious inputs and segmental and non-segmental noxious inputs. Convergence of excitatory a n d / o r inhibitory inputs from other viscera such as the esophagus [158], testis [319], gallbladder [158,159], colon/rectum [132,133,215,307,308] and vagina [132,133,177] also was a common finding. Studies by Fields et al. [158,159] revealed gross temporal correlations of neuronal activity with changes in blood pressure and consistently found that responses (excitatory, inhibitory) of neurons with axons in the ventrolateral quadrants of the cervical spinal cord preceded the changes in blood pressure. No attempts were made to link the intensity of bladder distension with the threshold for activation of cardiovascular responses. Cervero and lggo [93] utilized distension of the bladder as a conditioning stimulus and reported that it had no effect on spinocervical tract neurons in the cat. Cadden and Morrison [73] recorded from dorsal horn neurons in the lumbar enlargement of the rat and demonstrated that distension of the bladder led to the inhibition of class 2 cutaneous neurons. Similar work by Brennan e~ al. [69] demonstrated that bladder distension at~o had an inhibitory effect on primate spinothalaml ~ tract neurons in the T2-T5 spinal segments. These studies suggest that bladder distension activates mechanisms related to the phenomena of counter-irritation. Kidney and ureters Renal colic is thought to be secondary to ureteral ob,struction and subsequent distension of
the ureter and renal pelvis since t.his pain occurs clinically with kidney stones large enough to produce obstruction. Experimental work in humans [Lennander, cf., 273,391,396] has established that probing the pelvis of the kidney or distension of the ureters and pelvis produces pain localized to the flank and lower half of the abdomen of the stimulated side. Risholm [396] determined that an intraluminal pressure threshold of 29-79 cm H20 was necessary for the production of pain due to distension of the ureter and kidney pelvis and reported that sympathectomy abolished the pain. Ray and Neill [391] also reported that sympathectomy abolished pain due so ureteral distension or traction on the ureters or kidney pelvis/pedicle. They also noted that electrical stimulation or pressure applied to the renal capsule not bordering the renal pelvis was non-painful. Woodworth and Sherrington [490] were the first investigators to demonstrate that mechanical manipulation of the ureter could produce pseudoaffeetive responses in dogs. Their studies were most notable, however, for the lack of response to ureteral distension following hemisection of the contralateral spinal cord. Brasch and Zetler [67] developed an animal model of renal colic by cannulating the ureters of pentobarbital-anest.hetized rats and distending the renal pelvis to pressures of 80 mm Hg, producing reliable depressor responses that were attenuated/abolished by morphine (0.5-1 mg/kg; reversed by naloxone) or the decapeptide cerulein. Cardiovascular responses to ureteral distension, manipulation of the kidney and renal venous occlusion also have been documented by other investigators [e.g., 16,185,462], but by virtue of their use of selective analgesic drugs to modulate the responses, Brasch and Zetler [67] were the first to make a good case for these changes being representative of a visceral pain. Visceromotor responses also can be evoked by mechanical stimulation (pinch, poke) of the kidney [317]. Kostreva et al. [2491 reported that cardiovascular changes occur with renal vein occlusion, a finding confirmed aad extended by Ammons v,~o reported that ureteral or renal venous occlusion excited roughly half of 64 spinoreticular neurons in the cat [i6] and 38 spinothalamic neurons in the
200 primate [17c]; all spinal units in both studies were excited by renal nerve stimulation. All neurons excited by venous occlusion also were excited by meteral occlusion when tested for responses to both stimuli [16]. However, some neurons were excited only by ureteral occlusion and not venous occlusion; 100% of these neurons had somatic convergent receptive fields, most of which were class 3 in character [16].
Biliary system Pain arises from the gallbladder and biliary tract with obstruction of the cystic or common bile ducts, which elevates pressure (generally 35-45 mm Hg) within the biliary system [118,350]. Several investigators [391,501,502] were able to reproduce this pain by distending gallbladders in humans under local anesthesia and/or lightened general anesthesia or by distending a fistulated gallbladder via a cholecystostomy [359]. In these studies, distension or traction on the gallbladder led to deep, epigastric pain, inspiratory distress and vomiting as well as cardiovascular responses. A T-tube cannulating the biliary tract used to be commonly employed following cholecystectomy tor surgical drainage; this allowed ready access to the biliary system for researchers interested in studying sensation produced by distension of this system. Pain due to distension of the biliary system was reported to be identical to pain experienced pathologically [101,140] and was directly related to intraluminal pressure of the biliary tract [300] since pain was associated with pressure waves within the biliary system and was referred to the right upper quadrant of the abdomen, right scapula and right shoulder. Ravidin et al [390] reported that in patients with underlying coronary artery disease, distension of the common bile duct led also to precordial and upper li~(~ referral of pain. Distension of the biliary tract also produces rigidity of the abdominal wall, ins!firatory distress, nausea, vomiting and belching ['266] and cardiovascular change; 152,212,299,3~,2]. Spontaneous spasm of the spai ~cter of Oddi or that induced by morptfine leads to increases in pressure in the biliary system and ~ubsequcnt increases in pare sensation [266~3~0]. The inhalation of amyl nitrate l~roduces a ~ehxation within the bilia~ system ,
and a subsequent drop in intraluminal pressure and pain [300]. Ray and Neill [391] and others [483] have demonstrated that experimental pain due to stimulation of the gallbladder is blocked by bilateral splanchnectomy. Gaensler [179] quantitatively examined the relation between biliary intraluminal pressure and pain sensation in studies in 40 patients. Pain thresholds were documented to be reproducible and reliable within the same subjects; 17 different determinations over a period of 12 h revealed httle variability. By performing repeated measures on the same patients with T-tubes in place, Gaensler was able to demonstrate that pain thresholds (measured as intraluminal pressure) increased as inflammation within the biliary tract decreased. Pain thresholds were as low as 9 cm H,O (mean~ 43 cm H20 ) immediately following surgery, whereas pain thresholds varied from 20 to 80 cm H20 (mean, 54 cm H20) following recovery. Gaensler also demonstrated that administration of morphine and other opiates, but not aspirin, acutely increased the pressure threshold necessary to produce pain due to distension of the bihary system. Animal studies of pseudoaffective reflexes arising from distension of the biliary system were first reported by Woodworth and Sherrington [490]; they noted that injection of water into the bile duct of a dog produced facial reactiops and pressor responses of 14-36 mm Hg. Cervero reexamined these pressor responses in cats [86] and further demonstrated similar pressor responses to gallbladder distension in the r. . . . . ,n-. I,, sure thresholds for the pressor response observed by Cervero were 20-25 mm Hg and responses were graded with the distending pressure. In Cervero's study of the ferret, he demonstrated that biliary pressures of only 5-7 mm Hg produced relaxation of the sphincter of Oddi. Section of both greater splanchnic nerves was necessary to abolish the cardiovascular responses to distension of the gallbladder, although the effect of right splanchnic nerve section was predominant. Similar results incats had been noted previously by Newnian t.~ll Wind determined that the adrenal [~ands were responsible for much of the pressor response. Ammons and Foreman [23] also e x a ~ n e d pressor r~t=
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responses in the anesthetized cat produced by distension of the gallbladder while recording from spinal neurol~s ~md established a stimulus-response relaticr~ between distending pressure and pressor responses. Stulrajter et al. [443] noted that intensity-related alterations in heart rate occur in dogs with distension of the gallbladder, as have o!:hers [119,2i2,420]. Gallbladder distension, in addition to dis~or,~ion of the stomach, also has been reported to reduce coronary blood flow during distension [119,184]. Changes in respiration, to the point of chronic partial contraction of the diaphragm [420], have been noted by several investigators during mechanical stimulation of biliary structures [34,126,128,167,443]. These changes in respiration were abolished by se,ctioning the right greater splanchnic nerve [126,420] although omer responses to gallbladder distension, such as vomiting and increased salivation, were not, suggesting a vagal route for primary afferents related to these responses. An interesting finding of Davis et al. [126] was that anterolateral chordotomies did not abolish pseudoaffective reflex responses to gallbladder distension in dogs unless the lesions extended into the gray matter or the dorsolateral funiculi also were cut. In these dogs, simple anterolateral chordotomies produced somatic analgesia bat failed to produce visceral analgesia. These investigators interpreted the results to mean that visceral pathways within the spinal cord were different from somatic pain pathways and likely involved numerous short ascending connections. Gallbladder distension also has been shown to produce visceromotor responses in decerebrate cats [34] and in awake, unanesthetized cats and dogs [443]. Behavioral 'escape reactions' also were noted by Stulrajter et al. [443], but a precise definition of what constituted an 'escape reaction' was not described. Neurons responsive to distension of the gallbladder have been identified in the medulla [371], white matter axons ,in the cervical spinal cord [158,160] and in T1-T5 spinal segments of the primate [20] and T2-T4 [23] and T8-T9 [86,89]; spinal segments of the cat. In work consistent with his characterization of afferents from the gallbladder, Cervero [86,87,89] demonstrated that spi-
nal neurons excited by distension of the gallbladder only were excited at distending pressures greater than 10 mm Hg (i.e., above non-pathologic:li, physiological levels). In a group of 7 neurons, accelei-ating stimulus-response functions related intraluminal gallbladder pressure to neuronal response [86,89]; pressure thresholds for activation were 25-30 mm Hg and, therefore, likely in the noxious range. In the same studies by Cervero, cardiovascular responses were noted to begin at distending pressures of 30-45 mm Hg. Somatovisceral convergence was commcn. Of 30 neurons characterized by Cervero [89], 4 were class 1, 13 were class 2 and 7 were class 3; the cutaneous receptive fields for 6 neurons were not described. Cervero also demonstrated that neuronal responses secondary to distension of the gallbladder av_d hi!i~,3, ),'e,~ were not due t,) changes in portal venuus pressure [89] Another interesting finding was that although neurons located in spinal lamina I were excited by stimulation of the greater splanclmic nerv~, none were found that were excited by distension of the gallbladder [89]. Ammons and associates [20,23] characterized 17 spinal dorsal horn neurons in the cat and 13 spinothalamic tract neurons in the primate excited by gallbladder distension. Extrapolation of stimulus-response functions relating neuronal responses to the intraluminal pressure of distension revealed population mean thresholds for excitation of 0-10 mm Hg, presumably non-noxious intensities of stiraulation. Viscerosomatic convergence was 100% in these neuronal samples and all neurons were described as class 2 or class 3. In addition to excitatory responses to gallbladder distension, Ammons and Foreman [23] also noted that the spontaneous activity of 35% of the neurons were inhibited by gallbladder distension in an intensity-depend(rot manner. They also documented viscerovisceral convergence in neurons excited by gallbladder distension; these neurons also were excited by electrical stimulation of thoracic visceral nerves [20,23] a n d / o r the intraatrial injection of the algesic peptide bradykinin [20]. The findings of Cervero [86,89] and those of Ammons [20,23] suggest different neurophysiological understandings of visceral pain. Cervero's results support a specificity theory of visceral
202
nociception where some, if not all, spinal neurons excited by gallbladder distension can be excited only by pressures that are noxious and are thus dedicated to nociception. The findings of Ammons and associates indicate that spinal neurons are excited by both noxious and non-noxious intensities of gallbladder dister.sion. Why the pressure thresholds for excitation differ between these studies is not readily apparent. Both studies examined neurons with long ascending projections and cell bodies located deep in the spinal dorsal horn. It may be significant that the neurons studied by Ammons and associates [20,23] were spontaneously active while those studied by Cervero [86,89] were not. This could be due to differences in experimental preparation and/or neuronal samples. For example, Ammons and associates examined neurons in the upper thoracic spinal cord while Cervero examined neurons in the T8T9 spinal segments. Tonic descending influences or anesthetic effects may have been more predominant in Cervero's preparation. Alternatively, there may have been increased inflammation with sensitization/facilitation of responses due to the more extensive surgical interventions in the experimental preparations of Ammons (who also electrically stimulated thoracic visceral nerves). Testis Long b~fore they undertook their scie~,tific training, male investigators realized that compression of the testicles could produce intense pain. In 1933, Woollard and Carmichael [493] undertook the experimental study of pain arising from the testicles by performing various manipulations on themselves. By using known weights (50-1000 g) to compress a testicle, they reported that pain was referred to the groin, inside of the thighs and lower back. By selectively anesthetizing nerves innervating the scrotum and its contents, they were able to demonstrate that testicular pain was localized to roughly the T10-L1 spinal levels with information traveling predominantly through the superior spermatic nerve. Subsequent investigators have concentrated on animal models of testicular pain. Kumazawa, Mizumura and associates [e.g. 253.320] and others [382] have performed extensi~,: studies examining the mechano- and chemo-
sensitivity of testicular afferents in the dog. Compression of the testicle has been described as producing cardiovascular responses and changes in respiratory rate in rats [233] and dogs [320]. Mizumura et al. [320] reported intensity-related depressor responses and suppression-facilitation of respiratory rate, minute volume and phrenic nerve activity. Depressor responses were noted with low intensity compression (30 g) whereas alterations in respiratory rate did not occur until compression by 100 or 200 g. Testicular compression also excites primate spinothalamic tract neurons [319] and rat lumbar spinal neurons [233]. In a sample of 20 spinothalamic tract neurons located at the thoracolumbar junction in the primate, Milne et al. [319] reported that 17 (85%) of these neurons were excited by compression of the ipsilateral testicle; 5 spinothalamic tract neurons in the sacral spinal cord were tested and found to have no response to testiculez" compression. Responses to graded testicular compression were similarly graded and heating of the testicle or the application of an irritant chemical (isotonic KCI) to the exposed surface of the testicle also produced excitation in these neurons. All of the spinothalamic tract neurons with testieular input had convergent somatic receptive fields located on the flank and back. Four of the neurons excited by testicular compression were excited only by noxious cutaneous stimuli (class 3); the rest were excited by both noxious and non-noxious cutaneous stimuli (class 2). Viscerovisceral convergence with input from the ,finary bladder and colon also has been noted [319] (e.g., Fig. 12). Female reproductive organs Pain origLnafing from the female reproductive organs is a conunon experience: Mittleschmerz, menstrual cramps, childbirth, pelvic inflammatory diseases or endometlfosis directly afflict roughly half of the population at least once in their life. There are numerous clinical reports related to these forms of visceral pain and the relief thereof, but comparatively little experimental research. Javert and Hardy [225] attempted to quantify the pain of childbirth by asking women in labor to compare the intensity of pain experienced during different stages of labor with a radiant heat
203
A 10 Hz]
Jk 40 mmHg
.Jt., 80 mmHg
colorectal distension
I00 gm
200 gm
voginol probe
40 mmHg
80 mmHg
colorectol distension
press
squeeze
testis compression
Fig. 12. Viseerovisceral convergence. Examples of two thoracolumbar spinal dorsal horn neurons in the rat receiving excitatory input from multiple viscera. A: peristimulus time histograms of a neuron receiving graded excitatory input from both the colon/rectum and vagina/uterine cervix. B: similar representation of another neuron with convergent graded input from the colon/rectum and testicle. Cartoons of the corresponding convergent cutaneous receptive fields are also illustrated. Both units responded to innocuous brush and noxious pinch, heat and cold applied in the receptiw-, fidd [Ness, d Gebhart, unpublished].
stimulus measured in units of dols. Pain correlated with dilation of the cervix. Prior to cervical dilation, contractions were non-painful (e.g., BraxtonHicks contractions felt prior to actual labor). However, dilation of the cervix during labor led to incrementing, graded pain with a rough equivalent of 1 dol/cm of cervical dilation. The pain of full dilation (10 cm = ] 0.5 dols) was equivalent to pain evoked by radian~ heat sufficient to burn skin; dysmenorrhea was equated with 3-4 dols. These findings have been confirmed recently using multiple verbal and non-verbal instruments to assess labor pain [71a]. What research has been performed in animals has been predominantly concerned with the way in which perineal or vaginal stimulation affects sexual behaviors (e.g., lordosis [250]) and related endocrine function or has examined the phenomenon of vaginal stimulation-produced analgesia [e.g., 247]. In animals, postural changes ~nd alterations in respiration and gastrointestinal functiov_ occur with vaginal stimulation [e.g., 115,175, Ltori, cf., 175] and numerous spinal [133,250,389] and higher-order neurons [e.g., 177,217,401,402] are excited by vaginal probing, but specific relations to nociception arising from the vagina are not readily apparent. Viscerovisceral convergence w~h
input from the urinary bladder, colon and rectum has been demonstrated [133] (Fig. 12). Pinching of the ovaries or uterine horns or stretch of ovarian ligaments has been reported to produce cardiovascular and visceromotor responses [147]. Recent work by Berkley and her colleagues [49,50,50a] in the rat has focused on primary afferents arising from the uterus and travdilig in the hypogastric and pelvic nerves Hypogastric nerve afferents were found to be sensitive to probing, distension and natural contractions of the uterus and associated ligaments and also responded in a concentration-dependent fashion to injections into the', uterine artery of the algesic chemicals bra~ykinin, serotonin or KCI and the ischemia-anoxia-related compounds CO2 and NaCN. An interesting finding of these studies was that an apparent 'sensitization' of the afferents was necessary for them to become mechanosensitive, particularly ill relation to contractions of the uterus. Alterations h-i sensitivity also were found in association with the es'trous cycle. Other viscera
Mechanical! stimuli applied to other viscera inelude pinchin~ and rubbh~g of the peric~dium and heart [Capp% of, 273;10], sp!~:zn [105,147.31 "'].
204 diaphragm [78,274,328,393], mesentery [28] or pancreas [147274], producing reports of pain and cardiovascular, respiratory and/or visceromotor responses. Most notable of these is a study in humans by Morley [328] in which the peritoneal surface of the diaphragm was irritated with a probe or surgical mop during abdominal surgery under local or regional anesthesia, leaaing to reports of pain loc-,dized ~o the top of the shoulder (homosegmental to phrenlc nerve inputs). When the skin of one shoulder was infiltrated with novocaine, the reports of pain were much reduced or abolished on the side that was infiltrated while pain in the other shoulder was unaffected. It is possible to ascribe these results to spread of the local anesthetic to the phrenic nerve or to psychological causes, but analogous carefully controlled clinical or animal experimental s.~uries to refute or confirm studies such as this have not been performed. Distension of the thoracic aorta using an inflatable rubber cylinder coupled witli a rigid core cannula so that blood flow is not interrupted has been demonstrated by Malliani and associates [293,365] to produce strong pressor responses and tachycardia in awake, unanesthetized dogs in the absence of any discernible pain reaction. Restlesshess of the dogs was noted and was equated with similar behavior that occurs in response to excessive increases in arterial pressure induced by pressor drugs. A serendipitous finding of these same investigators [291] came from experiments in which the coronary arteries of dogs were chronically cannulated. In one dog the tip of the intracoronary catheter had slipped from the lumen of the vessel into the adjacent adventitia. Injections of r~ormal saline produced a local mechanical distortion of the vascular tissue and led to immediate and reproducible 'pain reactions' with vocalization and cardiovascular~ respiratory and visceromotor changes. Weaver et al. [475] reported alterations in renal sympathetic nerve activity with distension of the thoracic aorta and with mechanical stretching of the right or left ventricles of the heart (using appropriately placed rows of sutures). Several investigators [234,298,376,445,482] have r,,ported that traction on coronary vessels, both arterial and venous, produces pseudoaffective re-
sponses in awake un~,~esthetized dogs. The pseudoaffective responses consisted of leg stiffening, salivation, limping on the left forepaw, alterations in respiration and cardiovascular changes. These responses have traditionally been attributed to myocardial ischemia, although the studies of Martin and Gordham [298] and Katz et al. [234] specifically dissociated vascular occlusion from vascular traction by employing multiple ligatures. These investigators reported that pseudoaffective responses were evoked only with vascular traction and that vascular occlusion alone did not produce pseudoaffective responses. Further, they reported that traction or tearing of the myocardium did not produce pseudoaffective responses if traction of the vasculature did not occur. Blair and associates also examined sensation ari!i:iz~g from the heart by utilizing mechanical ~'probir.g of tile epicardium and pericardium, volume loading and artificially producing premature ventricular contractions (PVCs) to excite spinal [57] and medullary [55,56] neurons. Blair and Foreman [57] reported that all spinal neurons excited by PVCs received both A& and C-fiber input from thoracic visceral nerves, while most neurons not responsive to PVCs were excited exclusively by AS-fibers. Using a blunt wooden stick to probe and forceps to pinch the epicardium and pericardium, these same investigators reported that 13 of 21 neurons excited by stimulation of thoracic visceral nerves also could be excited by mechanical stimulation of the heart and associated structures and that 13 of 23 neurons tested were excited by occlusion of the aorta or pulmonary artery with resultant increases in intraventricular pressures. Most, if not all, primary afferents from the heart [e.g., 83,295,463] and some spiny neurons [e.g., 25,60] excited by elet:trical stimulation of the stellate ganglion or inferior cardiac nerve exhibit prose-related or cardiac volume-related activity, indicating mechanosensitivity. It has been suggested [292] that cardiac p fin may actually be due to abnormal mechanical distortion or dile:ion of areas of ischemic muscle (and adjacent vasculature) and/or the sensitization/activation of these mechanoreceptors by chemical mediators (e.g., bradyldnin, discussed below). This proposal would
205
be consistent with clinical observations of cardiac pain due to mechanical stimuli associated with mitral valve prolapse, but experimentally this assertio, is neither proven nor disproven. S u m m a r y - mechanical stimuli
Mechanical stimulation of organs such as the gastrointestinal tract has been used widely both in clinical and experimental studies of visceral sensations, including pain. Isolated, mechanical pinch of most organs does not reliably produce paix~ in ht~mans, but has been useful as a visceral stimulus for mapping neural pathways in animals. Distension of hollow organs has been a more useful stimulus since pain in huraans arises pathologically secondary to this stimulus and this pain is reported ~s identical in character to pain produced experimentally. Distension of the gut has been demonstrated to be aversive to rats, and distension of both the gut and other hollow organs produces strong pseudoaffective responses in multiple species. Distension also produces vigorous, reliable and reproducible neuronal responses and both neuronal and autonomic/motor responses t¢ distension of hollow organs are inhibited by analgesic drags and other antinociceptive manipulations. Mechanical stimuli such as distension of hollow organs therefore fulfill all criteria as adequate noxious visceral stimuli. Specific responses to distension must be considered only as representative of, but not necessarily specific for, visceral nociception since distension of hollow organs also produces non-nocieeptive autonomic reflexes.
lschemia as a noxious viscera! stimuim
Interruption of the blood supply to most deep tissues, including the viscera, often, but not always, leads to pain. Of great clinical concern is the interruption of the blood supply to the heart. Other pathological conditions resulting in pain secondary to ischemia/infarction are well described (e.g., mesenteric ischemia [386], torsion of spermatic cord [431], ischenfic colitis [272] and rectal angina [136]), although myocardial ischemia is clearly associated with the greatest morbidity
and mortality. In humans, angina occurs with increased cardiac work (increased heart rate, increased blood pressure) secondary to exertion, as in the treadmill test, or seconda~ to increased cardiac work, which occurs spontaneously during rest or sleep or following a myocardial infarction [e.g. 279,404]. In the case of exertic,nal angina it is cleat that increased cardiac work leads to ischemia (noted by electrocardiograohic changes) wlfich is then followed by pain. In the case of non-excrtio~ial angina, however, it is not always clear which occurs first, ischemia (due to coronary artery disease or thromboembolic event) and the subsequent activation of reflexes leading to increased heart rate and blood pressure, which in turn leads Ito increased cardiac work, more ischemia and subsequ~ng~ain (a positive feedback loop), or increased cardiac drive (for an unknown reason), leading to ischemia and then to pain. Positive feedback loops between the activation of cardi~.c afferents and sympathetic drive to the heart have been demonstrated in numerous studies by Mailiani and associates [e.go, 293,294]. Similar alterations in sympathetic tone and cardiovascular responses have been noted experimentally in animals during occlusion of coronary vessels [71,157,204, 252,296,473], although significant differences in preparation and results exist between and within studies. For example, one study [473] reported that occlusion of the left anterior descending artery of cats led to responses ranging from ch~lges in blood pressure of - 6 0 to + 85 mm Hg and alterations in sympathetic outflow to the kidney of - 4 0 to +90~, even though the experimental preparations were stated to be identical (a-chloralose anesthetized~ carotid sinus and aortic depressor nerves cut). Subtle differences in preparation, such as the depth of aJlesthesia, and previous experimental manipulations in the same animal may have contributed to this variability. The most reproducible autonomic responses to coronary artery occlusion have been observed in spinalized animals in which all brain-stem feedback controls have been severed [e.g., 71,296]. Several investigators have attempted to minimize the influence of anesthesia by examining the effects of coronary artery occlasion in awake uvanesthetized, lightly anesthetized (determined by
206 presence/absence of certain motor reflexes) or decerebrate preparations [70,234,298,323,445,481, 482]. These studies reported that occlusion of coronary vessels (arterial or venous) produced pseudoaffective responses consisting of cardiovascular changes, alterations in respiration, increased restlessness, increased salivation a n d / o r leg stiffening/limping. These responses began coincident ~t.h traction on the vessels and terminated as soon as the traction was released. A provocative finding of Sutton and Lueth [445] was that the accidental transection of a coronary vessel being occluded resulted in cessation of the pseudoaffective responses. That is, in spite of a complete cessation of blood flow, pseudoaffective responses were terminated, suggesting that cardiac pain is either due to mechanical traction upon vasculature or that nerves which carry cardiac nociceptive information from a specific region of the heart travel exclusively with the main coronary vessel supplying that region with no overlap from other nerves/vessels. As indicated earlier when reviewing mechanical stimuli, subsequent researchers using the preparation of Sutton and Lueth [234,298] dissociated the stimulus of vascular traction from occlusion of the vessel and reported that occlusion of coronary vessels without traction did not lead to pseudoaffective responses, but that traction without occlusion (using multiple ligatures pulling in 3 directions) did produce pseudoaffective responses. Thus, interruption of the blood supply to the myocardium may not be an adequate noxious stimulus, but traction on the blood vcs~el~ aione o~~coupled with ischernia is an adequate stimulus. To the best of our knowledge, the findings of these last two rarely cited papers have not been reinvestigated. Myocardial ischemia has been demonstrated in numerous studies to activate both myelinated and unmyelinated cardiac sensory fibers beginning 15-30 sec following occlusion of coronary vessels [e.g., 70,83,280,460,4661. Various investigators have attempted to relate this increase in activity with increases in local concentrations of endogenous compounds such as potassium, serotonin, bradykinin or prostaglandins, all of which also increase ~;ith cardiac ischemia [e.g., 62,204,238,478]. The relationship between these compounds and cardiac
ischemia only has been shown to be correlative since neuronal responses to bradykinin may be dissociable from responses to ischemia. Vogt et al. [466] were able to demonstrate that acetylsalicylic acid reduced the responses of cardiac afferents to the intraarterial administration of bradykinin but produced no reduction in responses of the same afferents to coronary artery occlusion. This study was not quantitative. However, similar studies by Longhurst and Dittman [282] in which abdominal afferents (gallbladder, pancreas, mesentery, liver, gut) excited by ischemia were examined, found that 10-20% of ischemia-sensitive fibers were not excited by intraarterial administration of bradykinin. There was a relation between the two stimuli as some of the abdominal afferents characterized by these investigators were sensitive to ischemia only after being 'sensitized' by bradykinin or prostaglandins; prior to exposure to these compounds, these abdominal afferents were not excited by ischemia. Neurons excited a n d / o r inhibited by coronary artery occlusion have been characterized in the spinal cord [58,171,456] and the medulla [53,54]. All of these studies examined the effects of coronary artery occlusion on the spontaneous activity of neurons that responded to the electrical stimulation of thoracic visceral nerves. Responses to occlusion were more commonly excitatory, but could be inhibitory, and were generally small in magnitude. Of 105 spinal neurons characterized by Foreman and Ohata [171]; less than half responded to coronary artery occlusion: 33 were excited, 3 were inhibited, 40 were unaffected and 29 unresponsive neurons were excluded from the study post hoc. Of the 33 neurons excited by coronary artery occlusion, 16 were excited at a latency of less than I sec, a time prior to the onset of any electrocardiographic changes, and hence these neurons were presumably mechanosensitive. The other 17 neurons began responding 2 sec or more following vascular occlusion, typically prior to the onset of electrocardiographic changes. The peak rate of activity during occlusion was compared with the mean rate of spontaneous activity (no values given) and an average increase in activity of approximately 9 Hz was reported. Blair et al. [58] reported that 17-20 of 33 spinal projection
207
neurons tested were excited by coronary artery occlusion and increased their activity from a mean spontaneous rate of 12 Hz to a mean peak rate during occlusion of 20 Hz. Other findings by Blair et al. [58] were similar to those of Foreman and Ohata [171]; spinal neurons excited during occlusion of coronary vessels had convergent cutaneous receptive fields centered in the dermatomes corresponding to the spinal segments of recording and hence located on the chest and upper limbs. Some of these spinal neurons were class 2 or 3, but exact numbers were not specified for neurons excited by occlusion. Obviously, experimental studies of myocardial ischenda are of potential clinical significance. Studies of spinal neurons receiving afferent input from the heart, however, suggest that even transient experimental manipulations may have profound effects on the responses measured and also alter other parameters (e.g., blood pressure, heart rate) that are not easily controllable. Hence, the difficulty in interpreting results from such experiments is apparent. For example, the character of the neuronal response to coronary artery occlusion may change with repeated experimental ischemic episodes [192a] (see Fig. 13). Clinical evidence suggests that cardiac pain is similar, if not identical, to other visceral pains in intensP.y and quality. However, given the fact that the heart is vital to the survivability of the organism, it is possible that special systems may have evolved to control cardiac pain and so are responsible for the phenomenon of 'silent' ischemia - - a clinical entity where ischemia of the myocardium is apparent electrocardiographically with no sensation of pain. Silent ischemia may not be unique to the heart, however, as infarcted bowel often does not become symptomatic until the onset of peritonitis. Studies in which ischemia/vascular occlusion have been used as visceral stimuli in other organs are few. Notable is a recent study by Ammons and Sinha [27a] in which 5570 of 67 neurons in the cat T11-T12 spinal cord excited by electrical stimulation of the renal nerve also were excited by occlusion of the renal artery. Similar to neuronal responses to coronary artery occlusion, these neurons exhibited responses coincident with the onset
|
]15 Hz
i st
3rd
5fh
I
i
7fh
t coronary.... t occlusions
Fig. 13. Visceroceptive neurons - ischemic sdmuh. The responses of a thoracic dorsal horn neuron in the cat to repeated coronary artery occlusions (left anterior descending artery) are illustrated as peristimulus time histo~ams representing responses to the 1st, 3rd, 5th and 7th occlusion; occlusionswere 60 sec in duration and administered every 10 rain. At bottom is a cartoon illustrating the convergent cutaneous receptive field of this neuron whichwas excited by noxious pinch [192a].
208
of occlusion (suggesting mechanoreceptive input) followed by a second response 30-60 sec later (presumably due to ischemia). Studies utilizing the distensior~ of hollow organs as a noxious stimulus also may be partially examining the effects of ischemia. For example, Ohman [360] reported that the blood flow within the small intestine of rats drops to near zero when the intraluminal pressure exceeds 60 mm Hg. Some studies have differentiated responses to ischemia from responses to distension [e.g., 452], but it is likely that ischemia has an effect on responses to repeated distensions. Pseudoaffective responses such as altered respiration and cardiovascular changes have been examined secondary to the occlusion of various abdorninal blood vessels [e.g., 47,414], but usually in the context of cardiovascular regulation by presumed abdominal baroreceptors or respiratory regulation by intestinal chemoceptors. Animal models of chronic mesenteric ischemia have been developed [e.g. 386], but at present these investigations have so~ght to examine the pathophysiology of this disease and have not specifically examined ischemia as a noxious stimulus. Modulation of responses tc coronary artery occlusion has been noted in one study by Pearcy et al. [376] in which the administration of morphine subjectively reduced pseudoaffective responses of dogs to coronary artery traction/occlusion.
Summary- ischemia Ischemia is a well-accepted etiology of pain from visceral tissues, particularly in the case of diseased oi ~ recently traumatized (post surgery) tissue, and may produce pseudoaffective responses in animals, hence fulfilling basic criteria as an adequate noxious viscera! stimulus. Ischemia is not, however, a reliable stimulus since ischemic myocardium or infarcted bowel is often 'silent' clinically and recognized solely by alterations in the electrocardiogram or the onset of associated symptoms such as peritonitis. Similarly, reflex and neuronal responses to ischemia also have exhibited marked variabi~ty within and between preparations. Some of the variability may be due to compensatory systems activated by the stimulus ~tself (e.g., opening of collateral vascular pathways), but because of the unreliability of re-
sponses to this stimulus, vascular occlusion is not ideal as a noxious visceral stimulus. Likewise, modulation or comparison of reflex or neuronal responses to ischemia-producing stimuli may be questionably meaningful in the presence of marked variability. It is possible that ischemia acts only as a modulator of mechanoreceptive visceral inputs and the variability observed in responses to ischemia may be due to the presence of preexisting pathology or mechanical distortion of the viscera secondary to a localized change in compliance/ muscle tone due to focal ischemia. Despite this difficulty in the control of and variability in responses to ischemia-producing stimuli, the clinical importance of ischemia in organs such as the heart necessitates continued, vigorous re,search with an emphasis on appropriate experimental controls.
Chemical stimuli as noxious visceral stimuli
General Algogenic substances have been used extensively to produce, by definition, pain in skin, muscle, ligaments and viscera. These substances have been applied topically to exposed surfaces and injected into the blood supply of various organs. The topical administratiou of algogenic substances limits the site of action to a well-localized isolated surface of the organ examined (e.g., epicardial surface). The intraarterial or intravenous (e.g., intr~porta!) injection o!' these substances produces activation of neural afferents in all layers of a given organ or group of organs, depending on the site of injection, but also may have systemic effects. Early studies, such as those by Moore and associates [322,323], investigated the sensibility of arteries and the visceral structures they supplied by injecting hypertonic saline, acidic or basic solutions of isotonic saline, lactic acid and various chloride, sodium or potassium salt solutions and observing pseudoaffective responses (respiratory changes, visceromotor responses and vocalization). Using this approach, they described pathways of visceral afferents to the spinal cord by performing selective lesions of nerves. For example, Moore and Singleton [323] injected isotonic KC1 and
209
lactic acid into the left coronary artery of cats and produced profound pseudoaffective responses. When the left sympathetic chain from the stellate ganglion to the .'1"7spinal level was removed, pseudoaffective responses did not occur until marked ventricular dilation (secondary to the lactic acid) and advanced asphyxia had developed. Lactic acid was used because it was felt to be 'physiological' (i.e., produced by Jschemic tissue). However, nonphysiological concentrations of up to 20% lactic acid were requi=ed to produce reliable pseudoaffective responses. Numerous other 'natural' compounds such as serotonin and potassium chloride also are algogenic, but again at questionably 'physiological' concentrations. However, bradykinin is a natural substance generated in response to tissue damage which is algogenic in concentrations assumed physiological. Bradykinin produces pain in humans when injected intracutaneously [e.g., 31,32, 113,218] or intraarterially [72,108,173,427]. In animals, using methods similar to those of Moore and associates, vocalization and pseudoaffective visceromotor responses, cardiovascular changes and respiratory changes are produced when bradykinin is administered intraarterially or intraperitoneally [137,194,195,275] in microgram dosages. Although the case for bradykirtin as an endogenous algogenic gubstance is strong, the precise role of bradykinin and its contribution to visceral nociception are not, as yet, completely defined. Bradykinin may not be the primary stimulus in visceral pain produced either mechanically or secondary to isehemia, but it clearly has modulatory effects on the same primary afferents and spinal neurons that are affected by these stimuli. Hence, bradykinin and other algogenic substances have been utilized extensively as noxious visceral stimuli.
Abdominal/pelvic organs Algogenic chemicals injected intraperitoneaUy have been the most widely used presumptive noxious visceral stimuli. The writhing test, a visceromotor response to the intraperitoneal administration of algesic chemicals, is commonly used in the screening of drugs, particularly novel or 'weak,' analgesic or ant[inflammatory drugs [e.g.,
2 ~•.,,,-,,,,-,-~, A1 '7 AA'71~.
It consists of characteristic visceromotor 'stretching' or 'writhing,' an alternating abdominal flexion-extension. Algogenic chemicals which have been employed include acetic acid, phenylquinone, hypertonic saline, bradykinin, serotonin, KCI, ATP, acetylcholkne and MgSO4 [e.g., 196,208,447], some of wtfich have been demonstrated to produce an acute peritoneal inflaz~artation [e.g., 357], presumably via a prostanoid mechanism [135]. Justification fgr the intraperitoneal administration of bradykinin as a noxious visceral stimulus was provided by Lim et al. [276] who examined the effects of intraperitone.,d injections of bradykinin in humaas. These investigators plzced a 20-30 cm long catheter petcutaneously into the peritoneal cavity and administered doses of 4-16 pg of bradykinin every 15 min for more than 2 h. Twenty-two percent of those people tested reported little or no pain, even after manipulation of the intraperitoneal catheter and repeated injections of 16 #g of bradykinin. These people were classified as hyporesponders and excluded from the study. Of those patients who did respond, objective measures of pain included grimacing and/or vocalization on the first injection of bradykinin; repeated injections led to reduced responses (tachyphylaxis). Subjective reports of pain were genelally of cramping or colicky pain, pressure/distension/ 'gas' pain or burning pain, alone or in combination. Aspirin, amphetamine and meperidine all gave pain relief to these individuals. Interestingly, aspirin given intraperitoneally was much more effective than when given orally, suggesting that responses to bradykinin are dependent on local inflammatory/prostanoid-related processes and not due to a direct action on chemosensitive nerve fibers. Pioneering research by Khayutin and associates [237] related chemosensitivity of the cat intestine (intraarterial injection of algogenic substances) to previously published pain thresholds in humans (cutaneous or conjunctival application of the same substances). Using a preparation in wlfich a loop of cat intestine was isolated and perfused (~ith nerves intact), these investigators were able to produce neurogenically mediated dose-dependent increases in systemic arterial blood pressure by
210
adding known concentrations of algogenic substances (e.g., KCI, capsaicin, bradykinin) to the intravascular intestinal perfusate. Brisk pressor responses were associated with concentrations of the algogenic substances previously demonstrated to produce pain in humans when injected into blister bases, intradermally or when applied to the conjunctiva. The use of chemic'efl!y similar, but nonalgogenic, substances such as t ryptophan led to weak dose-dependent pressor responses which these investigators attributed to noa-nociceptive reflexes. Frank [174] reproduced these findings and made a more extensive case for the neurogenic nature of the response. Other investigators have utilized similar techniques to restrict the application of algogenic chemicals to afferents from the small intestine [440,441], liver [35], spleen [75,194,195,275,311,458], stomach [281] and other abdominal organs [16a,224a,270] and examined their effects on cardiovascular parameters [16a, 35,74,224a,270,281,311,440,441,458], sympathetic nerve activity [74,311,440,441,458] or spinal unit responses [16a]. Cardiovascular responses were typically pressor, although mixed responses and even depressor responses [e.g., 35] were reliably produc,:d. A comparison of the cardiovascular responses on an organ-by-organ basis is confounded by differences in preparation and species. Several electrophysiological studies in which bradykinin or acetic acid was given intraperitoneally [e.g., 76,465] reported only inhibitory inputs to lumbar spinal and trigenfinal dorsal horn neurons. A study by Guilbaud et al. [192] selectively activated intestinal/colonic afferents by injecting bradykinin or acetylcholine interarterially into a collateral of the inferior mesenteric artery. Twenty of 20 spinal interneurons in the lower thoracic/ upper lumbar spinal segments excited only by non-noxious cutaneous stimuli were unaffected by the injections. Of 27 neurons excited by both noxious and non-noxious cutaneous stimuli (located predominantly in lamina V), 8 were excited by the injections, 14 were inhibited and 3 had mixed inhibito~j-cxcitatory responses. Other studies have demonstrated excitatory responses of spinal neurons to bradykinin excited by other v/sceral stimuli, such as colonic [e.g., 307,308,340, 343,345] or urinary bladder [307,308] distension.
,20sl15Hz
t
ep| Bk
t
AA Fig. 14. Visceroceptive neurons - chemical stimufi. Above, peristimulus time histogram illustrating the response of a thoracic dor~! horn neuron in a cat to the epicardial application (soaked pledget) of 10/Lg bradykinin (epi Bk). Below, a similar representation o£ the response of a sacral dorsal horn neuron in a rat to the appfication of a 5~ acetic acid solution (AA) to the colorectal mucosa. The corresponding convergent cutaneous receptive fields where pinch also gave excitatory responses are illustrated at the right [192a and Ness and Gebhart, unpublished].
Illustrations of typical neuronal responses to bradykinin are given in Fig. 14. A potentially confounding factor associated with the use of bradykinin to excite abdominal and pelvic afferents is that bradykinin may lead to a reflex contraction of smooth muscle. Floyd et al. [162,163] demonstrated that mechanoreceptors in the urinary bladder that were apparently excited by bradykinin were not chemoreceptive, but instead were excited secondarily to the reflex contraction of the bladder via a spinal reflex loop. Since distension or contractions of visceral smooth muscle produced by non-algogenic substances such as bethanecol [285,363] also lead to cardiovascular responses, the interpretation of responses to bradykinin must be carefully judged. Some investigators have reported that cardiovascular responses to bradykinin are greater than responses to bethanecol, even at dosages of bethanecol which produce markedly greater contractions of smooth
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muscle [e.g., 285]. An interesting tinding is that capsaicin, which affects substance P-containing nerve fibers, leads to strong cardiovascular responses but causes no co,-,.traetion of smooth muscle, suggesting that bradykinin and capsaicin may act on different populations of afferents. The topical admirdstrations of algogenic substances on the serosal .~urfaces of abdominal organs exposed by laparotomy are experimental analogues to the diffuse intraperitoneal injections ex~'.~'~! l~y L~,-~ ~-:. al. [276], but allow for more precise localization of the stimulus. Longhurst, Ordway, Weaver and associates all have demonstrated that the topical application of capsaicin a n d / o r bradykinin to the gallbladder [297,362, 413,438,468,469], stomach [285,297], pancreas [364] or small intestine [311,363,413,438,440,441,474] leads to sigrfificant respiratory changes [413,469], cardiovascular changes [285,297,311,362-364,438, 440,441,46~A74] and alterations in sympathetic nerve activity [311,440,44~,,,,-,1. " "" ~~ As v:ith the intravascular injection of algogenic substances, the reported cardiovascular responses have been varied, some investigators reporting consistent pressor responses, others depressor responses. Again, these differences appear to be species- or preparation-dependent and an organ-by-organ comparison between laboratories/preparations is of little value. The clear conclusion drawn from such studies is that chemical stimulation of the viscera produces pseudoaffective/autonomic responses. Numerous clinical observations in patients with esophagitis, gastric/peptic ulcers or gastritis indicate that chemical irritants such as stomach acid produce pain when in contact with inflamed mucosa. Unfortunately, most experimental studies restricted their use of algogenic substances to topical application to the external surface. Some studies did apply chemicals mucosally or intraparenchymally. For example, Smits and Brody [432] injected bradykinin into the substance of the kidney and reported cardiovascular responses. Giuliani et al. [186] reported similar responses with an application of capsaicin to the urinary bladder and Abelli et al. [3] evoked vigorous visceromotor responses with the instillation of xylene (10-100%) ii~to "-m~-urinary '-u~,~uu~r' - "~-' - - of rats.
Likewise, Ordway and Longhurst [362] were able to produce dose-dependent cardiovascular responses by applying bradykinin or capsaicin to either mucosal or serosal surfaces of the gall bladder. However, Longhurst et al. [285] were unable to produce cardiovascular responses by application of capsaicin or bradykinin to the stomach mucosa. 1'he application of algogenic substances to mucosal surfaces has been utilized clinically for years in the form of the widely employed Bernstein test [51]. In this test, 0.I N l:ydrochloric acid is infused onto the mucosa of the lower esophagus. Reports of chest pain and upper limb pain similar, if not identical, to cardiac angina resui~ when some form of pathology is present; normal, heaLLbv people typically do not experience pain in this test. Other human studies have applied algesic chemdcals to the mucosal surface of the stomach and observed mixed results [80,203]. Wolf and associates [cf., 203] reported that the application of acid, NaOH, mustard oil and other algogenic substances produced no responses from a patient when the mucosa of his stomach (reached via a gastrostomy) was pink and healthy. Distension pressure thresholds to produce pain from the stomach were near 35 mm Hg at these times. If, however, the mucosa was inflamed or engorged spontaneously or due to the application of mustard powder, these same substances produced marked pain (and resentment) and the distension pressure threshold for production of pain dropped to 20 mm Hg. Theobald [455] described a similar phenomenon; the application of a silver nitrate cautery or tongs to the uterine cervix produced no pain or sensation in 'healthy' females whereas the same manipulation in women sufferring from dysmenorrhea (i.e, had sensitized uterine tissue) produced abdomina! pain which radiated to the thighs, loins, groin and sacral back and was of sufficient intensity to xequire morphine. McLellan and Goodell [cf., 203] have described a similar phenomenon in the urinary bladder of humans and Grace, Wolf and Woolf [(~f 203] in the colon reached via a colostomy. Because human reports of pain due to the administration of algogenic substances to mucosa are dependent on preexisting pathology, this may explain why so few posi-
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tive experimental animal studies have been described. Recently, irritant chemicals have been infused into the lumen of hollow organs such as the esophagus [181], urinary bladder [197,246,305,306], colon (e.g., Fig. 1i) and pancreas [e.g., 259,400] to establish an inflarmnatory condition which eventually leads to visceral hyperalgesia or sensitization of a specifically chemosensitive subset of visceral primary afferents. McMahon and Abel [306] demonstrated that the urinary bladders of chronic decerebrate rats became hyperexcitable following treatment intracystally with turpentine, mustard oil or croton oil. Additionally, the rats also appeared to be hypersensitive to noxious stimuli applied to the tail or caudal abdomen (same spinal segments as urinary afferent input), but had inconsequential changes in responses to noxious stimuli applied to the hind limb or rostral abdomen, suggesting concomitant somatic hyperalgesia as is observed clinically in humans secondary to visceral pain. Simi!.arly, Garrison et al. [181] observed that acute inflammation of the esophagus produced by turpentine leads to a decreased volume threshold for activation and increased response of spinal neurons excited by esophageal distension. Clinically, inflamed viscera are the most common sources of abdominal visceral pain and so extensions of these studies will be of great basic scientific and clinical interest. Thoracic organs
Algesic chemicals, in particular bradykinin, have been widely employed in studies of cardiac nociception. Justification for the use of bradykinin to examine cardiac nociception is based on the correlative findings of Kimura et al. [238] and Hashimoto et al. [204] that the concentration of bradykinin increases in coronary sinus blood after the experimental occlusion of a coronary artery. As a consequence of these studies, numerous laboratories have employed bradykinin as a noxious stimulus to evoke cardiovascular responses [e.g., 156,190,294,356,366,394,435,436], ,?terations in sympathetic nerve activity [156,394] and responses in primary afferents [e.g., 38]. Pagani et al. [366] reported that in awake unanesthetized
dogs,which had been allowed to recover 3 weeks from intrathoracic surgery, the intracoronary administration of bradykinin (10-300 ng/kg) produced graded piessor responses but no 'pain ~actions' (e.g., vocalization, visccromotor responses), even at doses up to 2000 ng/kg. Bradykinin administered to acutely prepared, anesthetized dogs, cats or primates produced variable effects, suggesting sensitivity of the preparation to anesthetics or species differences. Malliani [291] suggests that a component of the variability of responses to visceral stimuli may be due to inputs from somatic structures, disrupted during the experimental surgical preparation. Neurons responding to the epicardial or intracardiac administration of bradykinin (e.g., Fig. 14) have been characterized by Blair, Foreman and associates in the medulla [53,56] and upper thoracic spinal cord [18,22,25,27,57,58,60,61,171, 456,476]. Like neuronal responses to coronary artery occlusion, responses to either the epicardial or intraatrial administration of bradykinin were observed to be relatively small in magnitude. For example, Blair et al. [60] reported that the activity of 30 of 41 primate thoracic spinothalamic tract neurons increased their mean discharge rate from 11 Hz to a mean peak response of 29 Hz. In a subsequent study in the cat, 36% of 64 spinal units were excited by intracardiac bradykinin, increasing in activity from a mean 4 Hz to a peak of 20 Hz [61]. Similar also to neuronal responses to occlusion of coronary arteries (e.g., Fig. 13), responses to bradykinin may change with repeated exposure. Blair and associates [60,61,476] observed that repeated administration of bradykinin led to markedly reduced responses (i.e., tachyp.hylaxis) in 517o of the total 67 neurons tested. Tachyphylaxis also has been noted previously in studies of cardiac primary afferents [e.g., 38] and confounds attempts to compare responses to bradykinin quantitatively. Whether tachyphylaxis to bradyldnin develops may be related to species a n d / o r the spinal unit studied. For example, Foreman [60 and personal communication] reports that reliable and reproducible responses to bradykinin are observed in - 6 0 % of primate spinothalamic tract neurons, but that responses of spinal neurons in the cat to the same stimulus are less reliable and
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not as reproducible. The interval between repeated testing and the dosage also likely coiitfibutes to the results. Dosages and routes of adm.,:nistration of bradykinin differ between studies and often within studies. Intervals between testing are often not controlled, but tachyphylaxis to bradyldnin is evident at intervals of 10 min and less [60,61,192a]. Similarly, Blair [53] observed that reticulospinal neurons generally did not respond to every application of bradykinin. Viscerosomatic convergence is presumed to be common in neurons excited by epicardial or intraatrial administration of bradykinin; the characteristics of these neurons have not been specifically described but instead grouped with the characteristics of numerous additional neurons responding to the electrical stimulation of thoracic visceral nerves. Similarly, the terminations of long ascending projections of neurons responsive to bradykinin have not been fully addressed, but spinoreticular and spinothalamic neurons form at least a subset of these neurons. Another interesting finding is that bradyldnin may produce a sensitization of some spinal neurons to cardiac mechanical stimuli, these neurons beginning to demonstrate pulse-phasic activity following the administration of bradykinin [25,60]. A troublesome finding of several experimental studies is that cardiovascular reflexes produced by epicardial or intraatrial administration of bradykinin began prior to the onset of a neuronal response. For example, the latency to the change in blood pressure produced by bradyldnin was significantly less than the latency to the onset of spinal unit responses [61]. Since the sample in this study was exclusively spinoreticular and spinothalamic tract neurons, these results suggest that these neurom are not related to the production of pseudoaffective responses and could potentially be excited secondary to the pseudoaffective responscs. Capsaicin also has been applied epicardially and into the coronary blood supply by Staszewska-Wooley et al. [437] with directly opposite effects. That is, epicardial application of capsMcin increased blood pressure and heart rate, whereas the intracoronary injection of capsaicin decreased blood pressure with a transient bradycardia. Fol-
lowing bilateral vagotomy, intracoroaary injection of capsaicin increased blood pressurc and heart rote, suggesting antagonistic effects of the activation of vagai and ~,y.mp~,,,,.,,,.t"~':" ..... ,,,.,.,~rr . . . . ~.,,,o'~ ,,r. . ~. ., m t h e heart. The other major organs of the thoracic cavity are the lungs. Studies of reflexes originating from the lungs are numerous, but studies of sensation are few. Recent reviews by Painta! [369] and Widdicombe [485] have poi:aed out that major gaps in knowledge exist in lung sensation. It is debatable whether pain ever originates directly from the lungs. Pain is often experienced in patients with lung cancer, but only after involvement of the pleura. Sensations or tightness, rawness, irritation or breathlessness can be attributed to the activation of afferents from the lungs and airways, but because studies of lung sensation have utilized the intravenous administration of chemi.~a!s such as lobuline or phenyldiguanide [e.g., 221], reports of gubsternal burning and discomfort are questionably of lung origin. Like the heart, because of their vital role in the survivability of the organism, the lungs may be affected differently by nociceptive stimuli and, because of their direct exposure to the external environment, have developed special protective reflexes to guard against noxious inhalants. The administration of substances such as capsaicin and phenyldiguanide into the lungs has been reported to produce cardiovascular and respiratory reflexes such as cough, sniffing and laryngospasm [e.g., 84,489], but other pseudoaffecrive responses such as vocalization or visceromotor reflexes have not been reported. Modulation Most studies of modulation of visceral pain produced by chemical stimuli have utilized the writlfing test described above. Although it has been used to examine endogenous analgesia systems [183], the writhing test has been used almost exclusively to evaluate the antinociceptivc or antiinflammatory efficacy of drugs. The efficacy of antiinflammatory drugs, specifically the salicyiates, in the writhing test is actually an argument against the test being representative of visceral pain since salicylates have very limited efficacy as analgesics for visceral pain in humans [161], with
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the exception of dysmenorrhea. This lack of efficacy is somewhat surprising since the salicylates and other antiinflammatory drugs are efficacious against deep pains arising in muscle, bone and joints and clinically it would appear that the etiology of much visceral pain is a sensitization of visceral structures by inflammatory processes. A major difference between the clinical and experim c n ~ situations is that experimentally, antimo flammatory drugs are given as pretreatments and so may effectively prevent inflammation before a presumed sensitization process starts. Clinically, antiinflammatory drugs are given after an inflammation has developed and so may only reduce (rather than prevent) inflammation and not affect the presumed sensitization process. Studies of abdominal [438] and cardiac [e.g., 436,461,466] afferents h~ve demonstrated that bradykinin-induced responses are significantly reduced by the administration of antiinflammatory drugs, an effect that can be reversed by the administration of PGEj, PGE 2 or PGI 2, but not by PGF2~ [438]. A facilitation of responses to the epicardial administration of bradykinin has been observed with the coadministration of PGE~ or PGE 2 [339,436]. It is possible that the contrasting effects of the intracoronary administration of bradykinin reported by Pagalfi et al. [366] in which vocalization and agitation were evoked in the immediate postsurgical recovery period (products of inflammation present), but were absent after additional healing, represent a sens',tizing, facilitatory or per~r.issive effect of prostaglandins on bradyldnin-sensitive visceral afferents. ~pinal neurons excited by the intracardiac administration of bradykinin have been demongtrated to be subject to inhibition produced by electrical stimulation of the vagus nerve [18,19, 456], nucleus raphe magnus [22], periventricular gray in the diencephalon [27], PAG in the midbrain [99], dorsolateral pons [68] and distension of the urinary bladder [69]. Stein et al. [440] reported that the pretreatment of adult rats with capsaicin led to a reduction in the cardiovascular aad sympathetic nerve responses to the topical administration of bradykinin to the small intestine and Abelli et al. [3] have reported that morphine (2-5 mg/kg s.c.) and baclofen (2.5-10 m g / k g s.c.) produced
dose-dependent inhibition of the visceromotor response to intracystal xylene. Summary - chemical stimuli
The administration of algogenic substances to viscera leads to autonomic, visceromotor and neuronal responses suggestive of nociception and, when administered intraperitoneally in humans, produces reports of pain in approximately 8070 of individuals tested. Hence, chemical stimuli injected intraperitoneaUy fulfill criteria as adequate noxious visceral stinmli. Presumably, they also are noxious when administered elsewhere and by different routes. Foremost of the algogenic substances is bradykinin, which is a natural compound formed during tissue damage. Frank tissue damage (e.g., cutting, burning) does not reliably produce reports of visceral pain, but does result in the production of bradykinin. This observation, coupled with reports that the intracoronary injection of bradykinin in the absence of associated pathology (e.g., post-surgical trauma) does not produce behavioral responses suggestive of pain, suggests that bradykinin is not sufficient as an adequate, noxious visceral stimulus. Reports of sensitizing effects of bradykinin on mechanosensitire primary afferents and dorsal horn neurons suggest that bradykinin may act as a modulator or co.stimulant of visceral sensory systems rather than as a primary stimulus. Neuronal respomes to bradyldnin arc not reliably reproducible. Hence :h~ util~ty of ~his stimulus ~or quantitative studies investigating the substrates or modulation of visceral nociception is limited to cases where the dosage and interval between dosages is controlled and responses are established as reproducible.
Final summary and comments Models o f visceral pain
Clinically, visceral pain can be sun~'narized as follows. Disease originating in the viscera leads to pain which initially is dull, achy and poorly localized. Eventually, pain becomes more localized and is "referred' to those somatic structures with afferents entering the same spinal segments as the afferents from the viscera; hyperalgesia in those
215 same somatic structures may be associated with the visceral pain. Additionally, disease processes originating in the viscera may spread to involve the parietes (somatic pleura and peritoneum) and so may be associated with referred/localized pain and hyperalgesia of somatic origin. Associated with both visceral and parietal pain are strong motor reflexes which may lead to muscle spasm and additional localized/referred pain and hyper~ algesia of somatic origin. Needless to say, the clinical picture of pathological 'visceral' pain is not simple and often involves pain of both somatic and visceral origins. Regardless, both human and non-human experimental investigations of visceral pain have been performed in the context of theories utilizing 'simple' mechanisms to explain all observations. Theorists of visceral pain diverge into 2 main groups historically, the pefipherafists and the centralists. Sturge in 1883 [444] first promoted the centralist hypothesis that activation of visceral afferents set up a 'commotion' in the gray matter of the spinal cord, leading to strong autonomic and motor reflexes. Sturge's ideas were further refined by investigators such as Ross [403], Head [207] and others to be finally stated in 2 main forms: by MacKenzie [287] as the 'irritable focus' or convergence-facilitation theory, in which the activation of visceral afferents leads to changes in the excitability of multiple spinal units, including those responsible for segmental motor outflow and somatic nociceptive sensc,ry pathways, but not to the direct activation of spinal neurons; and by Ruch [408] as the convergence-projection theory, in which the excitation of visceral afferents leads to the direct activation of neurons receiving both visceral and somatic inputs with cell bodies in the spinal cord and long ascending projections to the brain, specifically to the thalamus. In Ruch's convergence-projection theory, the brain misinterprets activity in the viscerosomatic neurons as indicating excitation of somatic afferents since visceral inputs are normally silent. Other variations on centralist themes propose that viscerosomatic convergence occurs exclusively at thalamic or cortical levels. Periphera!ist theories of visceral pain propose that vasoactive or 'sensitizing' factors are released
into cutaneous ~nd deep somatic tissues, leading to hyperalgesia and/or tonic 'referred' pain from those structures [e.g., 127]. Peripheralist theories also fell into 2 main ~oups: those stating that axon reflexes in sensory neurons with dichotomizing fibers projecting to both somatic and visceral structures were responsible for the release of these factors, and those stating that increased sympathetic motor activity was responsible for the release of these factors. Proposed wiring diagrams are varied and include sensory neurons with dichotomizi,g fibers branching to cutaneous, deep somatic and visceral tissues [479], sensory neurons with dichotomizing fibers having branches to visceral and somatic deep tissue paired with others branching to somatic deep tissues and skin (i.e., visceral stimuli produce deep tissue hyperalgesia which produces cutaneous hyperalgesia [430]), sensory neurons with direct excitatory connections with postganglionic, prespinal, ~ympathetic motor neurons [377], and neurons producing excitation of spinal preganglionic sympathetic motor neurons vi~ direct or polysynaptic connections. Support for both peripheralist and centralist theories derives from numerous clinical experiments using virtually identical approaches and obtaining relatively similar outcomes, but having radically different interpretations. Using local anesthetics or nerve sections to abolish/attenuate cutaneous (and likely deep tissue) sensation in humans, investigators reported that both pathological and experimental visceral pain was typically attenuated [66,110,141,229,328,455,477,494]. The peripheralists pointed out that the visceral pain was 'markedly' attenuated in these studies and that somatic pain typically outlasted the presentation of experimental visceral stimuli [e.g., 78]. The centralists pointed out that viscerosomatic pain was immediate in onset with experimental stimuli and could not be comp!etely abolished by peripheral manipulations. In most of these early studies it was unclear whether the visceral pain studied was pain referred to somatic structures or pain originating in hyperalgesic somatic structures. An example is provided in a case report by Cohen [110] iv which a patient with angina localized pain to an amputated 'phantom' limb prior to the onset of pain in his chest. Following a
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regional block of the brachial plexus, this patient then experienced anginal pain initially in the chest and later in the 'phantom' limb. Cohen also reported that blistering of the skin or injection of hypertonic saline intradermally led to a somatic hyperalgesia and that visceral pain previously localized to other homosegmental sites became referred to the sites of hyperalgesia. These findings, and those of others using local anesthesia or nerve transection, suggested that visceral pain has two components, one central and the other peripheral, or, alternatively, that central nervous system alterations in excitability occur which are affected by a summation of tonic visceral and somatic inputs. At present there exists neuroanatomical, dectrophysiological, behavioral and physiological evidence that supports components of all theories related to the localization of visceral pain. There is evidence for the existence of dichotomizing fibers in the periphery, although they are clearly insufficient in number to account for viscerosomatic convergence. There is also considerable support for Ruch's convergence-projection hypothesis since numerous spinal dorsal horn neurons having both visceral and somatic inputs and long ascending projections to the brain have been identified. There is support for M~cKenzie's convergence-facilita. tion hypothesis since clinically and experimentally, some responses to visceral stimuli increase with repeated or sustained exposure. There is also support for theories related to increased sympathetic motor activity; visceral stimuli excite sympathetic preganglionic motor neurons in the spinal cord and directly activate sympathetic postganglionic neurons through direct connections in autonomic ganglia. Further, increases in sympathetic outflow have been related to pathological hyperalgesia phenomena such as reverse sympathetic dystrophy syndrome.
A proposed model of visceral pain In an attempt to reconcile these various theories of visceral pain with clinical observations and the experimental results reviewed here, the following model of visceral pain is proposed. It is acknowledged that the model is incomplete and does not adequately describe all of the compo-
nents of visceral pain. However, it is consistent with observations to date and its components are testable and so it will serve as our guide in the formulation of specific questions related to visceral pain. The first component of this model is a synthesis of Ruch's convergence-projectioa theory and MacKenzie's convergence-facilitation theory and describes the referral of visceral pain to somatic structures. The second component of this model describes the phenomenon of somatic tissue hyperalgesia that occurs in association with visceral pain and which is best explained by peripheralist theories. Visceral pain is encoded in the activity of dorsal horn neurons activated directly by visceral and somatic primary afferents and also indirectly via recurrent modulatory neuronal loops involving both spinal and brain-stem components. The activity of dorsal horn neurons in response to a noxious visceral stimulus is a function of the number of sensory afferents to the spinal cord activated by that stimulus, the frequency and duration of the activity of these afferents, and the basal excitability of the neurons receiving this input. The activity of the afferents to the spinal cord and the excitability of dorsal horn neurons receiving visceral input are increased with repeated or persistent (pathological) noxious visceral stimuli due (1) to a sensitization of afferents which occurs secondary to local mechanisms in the viscera (e.g., chemical mediators related to tissue damage and/or ischemia) and (2) to a facilitation of dorsal horn neuronal responses which occurs via central mechanisms identical to those observed by Woolf and associates [e.g., 491] in response to deep tissue afferent inputs. The degree of facilitation is dependent on the immediately preceding activity in the afferents since a critical level of afferent activity is required before the mechanisms of facilitation come into play. Hence, visceral pain does not occur in response to localized or brief stimuli because the activity of dorsal horn neurons encoding visceral nociception is due to more than the spatial and simple temporal summation of polymodal visceral afferent activity. In most cases, visceral pain is dependent on the sensitization of afferent inputs and a facilitation of dorsal horn neurons to these afferent inputs; both sensitiza-
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tion and facilitation take time to become estabfished and both outlast the stimulus. If a sufficiently large area of visceral tissue is stimulated intensely enough, pain may be sensed prior to the development of sensitization or facilitation, but this typically is not the case. The referral of visceral pain to somatic structures is due to viscerosomatic convergence onto at least 2 main classes of spinal neurons receiving afferent inputs from all deep tissues represented at a particular spinal segment: one group of these neurons is involved in the localization Gf pain and projects to the brain while at least one other group of neurons has short ascending projections and/or long ascending projections with collaterals projecting into multiple spinal segments. Initially, visceral pain is poorly localized, dull and achy due to the wide divergence of visceral afferents in the spinal cord. In comparison with the surface of the body, the viscera are sparsely innervated by afferents to the spinal cord. Individual visceral afferents weakly activa~ .~econd-order spinal neurons in numerous spinal segments, some relatively distant. Primary afferents from cutaneous structures do not diverge as widely within the spinal cord and, moreover, there exist somatic primary afferents which are nociceptive specific. The stimulation of only a few of these cutaneous afferents results in a high level of excitation of relatively few dorsal horn neurons, resulting in the consequent well-localized pain. Activity in cutaneous afferents does not facilitate responses of dorsal horn neurons in the same way as deep tissue afferents. Poorly localized visceral pain becomes better localized as visceral afferent input increases due to the process of facilitation and/or activation of specific or 'silent' nociceptors. The greatest localization occurs when somatic structures (e.g., parietes) become involved in the painproducing process (e.g., with spread of infection). The hyperalgesia in cutaneous and deep tissues that occurs in association with visceral pain is a combination of increased sympathetic outflow, due primarily to direct visceral affere~ connections in the prespinal ganglia, and secondarily to axon reflexes arising in axonal extensions to both visceral and somatic structures. Manipulations which produce pain relief in conditions such as
reverse sympathetic dystrophy syndrome will lead to relief of the somatic hyperalgesia associated with visceral pa~n. This is an admittedly and purposely speculative model of visceral pain, but it has some support from the scientific and clinical literature. Studies to date have been predominantly descriptive and only a few, such as those using analgetic drugs, are truly experimental in that a hypothesis was proposed and specific endpoints measured. This model of visceral pain is presented so that specific questions can be asked by ourselves and others to address quantitatively whether there is support for these speculations.
Directions for research As stated earlier, experimental investigations of visceral pain have addressed 5 main topics: the nature of the adequate stimulus for pain production, the site of its action, the distribution of pain nerve endings in the viscera, the peripheral and central pathways which lead from viscus to sensorium, and the mechanisms involved in the localization of visceral pain. To date, none of these aspects of visceral pain has been definitively characterized. Numerous qualitative studies have identified probable components of visceral pain processing, but pending quantitative analysis by experimental studies, particularly psychophysiological studies, limited progress will be made towards a scientifically based cnderStandmg of visceral pain or the rational development of new therapies to treat it. Subjective generalities and anecdotal examples are, and always have been, of limited scientific value. Strict definitions of both stimuli and responses to those stimuli are required. The literature reviewed here contains numerous examples where the term 'response' was never defined and in many studies 'responsive units' were grouped as though functionally the same, despite tl~e demonstration that individual units in some reports had opposite responses to a given visceral stimulus. Even when 'defined,' criteria for 'response' included such characterizations as 'looking like a response.' Simple qualitative descriptions of neuronal, reflex and behavioral responses to visceral stimuli have been useful as they have idcr,:ified
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generalities of visceral sensation tha~ now need to be investigated more rigorously. In the hope of facilitating the process of scientific definition of visceral pain, we propose the following criteria as necessary for a valid, adequate, noxious, visceral stimulus: (1) the stimulus must produce pain in humans experimentally and ideally be related to p~.thological pain; (2) the stimulus must alter the behavior of the experimen-. tal subject in a way consistent with an interpretation that the stimulus is aversive (i.e., the animal changes behavior to avoid the onset or continuation of the stimulus); (3) the stimulus must evoke basic physiological 'pseudoaffective' reflexes consistent with what occurs in humans in response to visceral pain; and (4) responses to the stimulus must be modulated by antinociceptive manipulations (e.g., morphine) in a way consistent with the clinical effects of the same manipulations in humans experiencing visceral pain. These criteria obviously emphasize that animal models must closely mimic the human situation and are simple extensions of previously accepted criteria for noxious stimuli stated at the beginning of this review. However, the criteria listed above require experimental proofs and are testable. Stimuli used in experimental studies of visceral pain also should be controllable, quantifiable, reproducible and, ideally, graded. Responses to these stimuli should be reliable and, following characterization, predictable, although not necessarily identical from trial to trial. If responses are not reliable, studies of their modulation are of little value scientifically since it is unclear what is being examined, modulation or the unreliability of responses. Thus, if the neuronal substrates of visceral sensation are to be understood based on the study and characterization of responses (in order to make comparisons with complimenta~ ps:~chophysiological studies in humans), then the stimuli used to activate these neurons must be reproducible and the responses as reliable and predictable as are human responses to the same stimuli.
Acknowledgements The authors gratefully acknowledge the graphics
produced by Mike Burcham, the secretarial assistance of Kathryn Renbarger and Marilynn Kirkpatrick and the critical comments or, earlier versions of this essay by Jayne Ness. The authors have been supported by DHHS Awards NS 19912, NS 24598, H L 32295, DA 02879, a Life and Health Insurance Medical Research Fellowship (T.J.N.) and an unrestricted Pain Research Grant from Bristol-Myers Squibb. References 1 Aars, H. and Akre, S., Reflex changes in sympathetic activity and arterial blood pressureevoked by afferent stimulation of the renal nerve, Acta Physiol. Scand., 78 (1970) 184-188. 2 Abrahams, V.C. and Swett, J.E., The pattern of spinal and medullary projections from a cutaneous nerve and a muscle nerve of the forelimb of the cat: a study using the transganglionic transport of HRP, J. Comp. Neurol., 246 (1986) 70-84. 3 AbeUi, L., Conte, B., Somme, V., Maggi, C.A., Girliani, S. and Meli, A., A method for studying pain arising from the urinary bladder in conscious, freely-moving rats, J. Uroi., 141 (1989) 148-151. 4 Acheson, G.H., Rosenblueth, A. and Partington, P.F., Some afferent nerves producing reflex responses of the nictitating membrane, Am..I. Physiol., 115 (1936) 316-320. 5 Aidar, O., Geohogan, W.A. and Ungewitter, L.H., Splanchnic afferent pathways in the central nervous system, J. Neurophysiol., 15 (1952) 131-138. 6 Akeyson, E.W. and Schramm, L.P.. Viscerosomatic convergence at two levels of the rat spinal cord, Neurosci. Abst., 14 (1988) 727. 7 Albano, J.-P. and Gamier, L., Buibo-spinal respiratory effects originating from the splanchnic afferents, Resp. Physiol., 51 (1983) 229-239. 8 Alderman, A.M. and Downman, C.B.B., Reflex activation of intercostal nerves and trunk muscles by non-myelinated fibres of the splanchnic nerve in rabbits, J. Physiol. (Lond.), 150 (1960) 463-477. 9 Alexander, W.F., The innervation of the biliary system, J. Comp. Neurol., 72 (1940) 357-369. 10 Alexander, W.F., M,~,:Lcod, A.G. and Barker, P.S., Sensibility of the exposed human heart and pericardium, Arch. Surg., 19 (1929) 1470-1483. 11 AI!es, A. and Dora, R.M., Peripheral sensory nerve fibers that dichotomize to supply the brachium and the pericardium in the rat: a possible morphological explanation for referred cardiac pain, Brain Res., 342 (1985) 382-385. 12 Amassian, V.E., Cortical representation of visceral afferents, J. Neurophysiol., 14 (1951) 434-444. 13 Amassian, V.E., Fiber groups and spinal pathways of cortically represented visceral afferents, J. Neurophysiol., 14 (1951) 445-460.
219 14 Ammons, W.S., Renal afferent input to thoracolumbar spinal neurons of the cat, Am. J. Physiol., 250 (1986) R435-R443. 15 Ammons, W.S., Characteristics of spinoreticular and spinothalamic neurons with renal input, J. Neu~-ophysiol., 58 (1987) 480-495. 16 Ammons, W.S., Spinoreticular cell responses to renal venous and ureteral occlusion, Am. J. Physiol., 254 (1988) R268-R276. 16a Ammons, W.S., Spinoreticular cell responses to intrarenal injections of bradykinin, Am. J. Physiol., 255 (1989) R994-R1001. 17a Ammons, W.S., Renal and somatic input to spinal neurons antidromically activated from the ventrolateral medulla, J. Neurophysiol., 60 (1988) 1967-1981. 17b Ammons, W.S., Electrophysiological characteristics of primate spinothalamic neurons with renal and somatic inputs, J. Neurophysiol., 61 (1989) 1121-1130. 17c Ammons, W.S., Primate spinothalamic cell responses to ureteral occlusion, Brain Res., 496 (1989) 124-130. 17d Ammons, W.S., Responses of primate spinothalamic tract neurons to renal pelvic distension, J. Neurophysiol., 62 (1989) 778-788. 18 Ammons, W.S., Blair, R.W. and Foreman, R.D., Vagal afferent inhibition of spinothalamic cell responses to sympathetic afferents and bradykinin in the monkey, Circ. Res., 53 (1983) 603-612. 19 Ammons, W.S., Blair, R.W. and Foreman, R.D., Vagal afferent inhibition of primate thoracic spinothalamic neurons, J. Neurophysiol., 50 (1983) 926-940. 20 Ammons, W.S., Blair, R.W. and Foreman, R.D., Responses of primate T1-T5 spinothalamic neurons to gall bladder distension, Am. J. Physiol., 247 (1984) R995R1002. 21 Ammons, W.S., Blair, R.W. and Foreman, R.D., Greater splanchnic excitation of primate T1-T5 spinothalamic neurons, J. Neurophysiol., 51 (1984) 592-603. 22 Ammons, W.S., Blair, R.W. and Foreman, R.D., Raphe magnus inhibition of primate T1-T4 spinothalamic cells with cardiopulmonary visceral input, Pain, 20 (1984) 247260. 23 Ammons, W.S. and Foreman, R.D., Cardiovascular and T2-T4 dorsal horn cell responses to gallbladder distention in the cat, Brain Res., 321 (1984) 267-277. 24 Ammons, W.S. and Foreman, R.D., Responses of T2-T4 spinal neurons to stimulation of the greater splanchnic nerves of the cat, Exp. Neurol., 83 (1984) 288-301. 25 Ammons, W.S., Girardot, M.N. and Foreman, R.D., Effects of intracardiac bradykinin on T2-T5 medial spinothalamic cells, Am. J. Physiol., 249 (1985) 147-152. 26 AwJnons, W.S~, Girardot, M.N. and Foreman, R.D., T2T5 spinothalamic neurons projecting to medial thalamus with viscerosomatic input, J. Neurophysiel., 54 (1985) 73-89. 27 Ammonia, W.S., Girardot, M.N. and Foreman, R.D., Periventric~dar gray inhibition of thoracic spinothalamic cells
projecting to medial and lateral thalamus, J. Neurophysiol., 55 (1986) 1091-1103. 27a Ammons, W.S. and Sinha, R., Responses of thoracolumbar spinal neurons to renal artery occlus~ion, Am. J. Physiol., 256 (1989) H1515-H1523. 28 Andrews, C.J.H., Andrews, W.H.H. and Orbach, J., A sympathetic reflex elicited by distension of the mesenteric venous bed, J. Physiol. (Lond.), 226 (1972) 119-131. 29 Andrews, P.L.R., Vagal afferent innervafion of the gastrointestinal tract. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 65-86. 30 Applebaum, A.E., Vance, W.H. and Coggeshall, R.E., Segmental localization of sensory cells that innervate the bladder, J. Comp. Neurol., 192 (1980) 203-209. 31 Armstrong, D., Dry, R.M.L., Keele, C.A. and Markham, J.W., Observations on chemical excitants of cutaneous pain in man, J. Physiol. (Lond.), 120 (1953) 326-351. 32 Armstrong, D., Jepson, J.B., Keele, C.A. and Stewart, J.W., Pain producing substance in human inflammatory exudates and plasma, J. Physiol. (Lond.), 135 (1957) 350370. 33 Ashkenaz, D.M., An experimental analysis of centripetal visceral pathways based on the visceropannicular reflex, Am. ~. Physiol., 120 (1937) 587-596. 34 Ashkenaz, D.M. and Spiegel, E.A., The viscero-parmicular reflex, Am. J. Physiol., 112 (1935) 573-576. 35 Ashton, J.H., lwamoto, G.A., Longhurst, J.C. and Mitchell, J.H., Reflex cardiovascular depression induced by capsaicin injection into canine liver, Am. J. Physiol., 242 (1982) H955-H960. 36 Bahr, R., Blumberg, H. and J~nig, W., Do dichotomizing fibers exist wi~h s~pply visceral organs as well as som~ ~ie structures? A contribution to the problem of referred pain, Neurosci. Left., 24 (1981) 25-28. 37 Bain, W.A., Irving, J.T. and McSwiney, B.A., The afferent fibers from the abdomen in the splancl,-iic nerves, J. Physiol. (Lond.), 84 (1935) 323-333. 38 Baker, D.G., Coleridge, H.M, Coleridge, J.C.G. and Nerdrum, T., Search for a cardiac nociceptor: stimulation by bradykinin of sympathetic afferent nerve endings in the heart of the cat, J. Physiol. (Lond.), 306 (1980) 519536. 39 Bardos, G. and Ado.m, G., Visceroceptive control of operant behavior in rats, Physiol. Behav., 20 (1978) 369-375. 40 Bardos, G., Nagy, J. and Adam, G., Thresholds of behavioral reactions evoked by intestinal and skin stimuli in rats, Physiol. Behav., 24 (1980) 661-665. 41 Barish, C.F., Castell, D.O. and Richter, J.E., Graded esophageal balloon distension: a new provocative test for noncardiac chest pain, Dig. Dis. Sci., 31.(198o) 1292-1298. 42 Barja, F. and Mafllison, R., Sensory irmewation of the rat portal vein and the hepatic artery, J. Auton. Nerv. Syst., 10 (1984) 117-125. 43 Baron, R., J~.nig, W. and McLacldan, E.M., The afferent and sympathetic components of the lumbar spinal outflow
220
44
45
46
47 48
49
50
51
52
53
54
55
56
57
58
59
60
to the colon and pelvic organs in the cat. I. The hypogastric nerve, J. Comp. Neurol., 238 (1985) 135-146. Baron, R., J~tig, W. and McLachlan, E.M., The 'afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. II. The lumbar splanchnic nerves, J. Comp. Neurol., 238 (1985) 147-157. Baron, R., J~mig, W. and McLachlan, E.M., The afferent and sympathetic components of the lumbar spinal outflow to the colon and pelvic organs in the cat. III. The colonic nerves, incorporating an analysis of all components of the lumbar prevertebral outflow, J. Comp. Neurol., 238 (1985) 158-168. Bayliss, J.H., Kauntze, R. and Trounce, J.R., Observations on distension of the lower end of the esophagus, Quart. J. Med., 24 (1955) 143-153. Bean, J.W., Intestines in reflex chemical control of breathing, Am. J. Physiol., 171 (1952) 522-527. Bentley, F.H. and Smithwick, R.H., Viscer~ pah'~ produced by balloon distension of the jejunum, Lancet, i-ii (1940) 389-391. Berldey, K.J., Robbins, A. and Sato, Y., Afferent fibers supplying the uterus in the r~t, J. Neurophysiol., 59 (1988) 142-163. Berkley, K.J., Robbins, A. and .Sato, Y., Sensory input from contractions of the uterus in the rat, Neurosci. Abst., 14 (1988) 727. Bernstein, L.M., Fruin, R.C. and Pacini, R., Differentiation of esophageal pain from angina pectoris: role of the esophageal acid perfusion test, Medicine, 41 (1962) 143162. Bettman, R.B. and Rubinfeld, S.H., Gallbladder-heart reflexes in man under spinal anesthesia, Am. Heart J., 10 (1935) 550-552. Blair, R.W., Noxious cardiac input onto neurons in medullary reticular formation, Brain Res., 326 (1985) 335-346. Blair, R.W., Cardiac input to medullary reticular formation: neuronal respo.-ses to CAO, Am. J. Physiol., 251 (1986) R670-R679. Blair, R.W., Cardiac input to medullary reticular formation: neuronal responses to mechanical stimuli, Am. J. Physiol., 251 (1986) R680-R689. Blair, R.W., Responses of feline medial medullary reticulospinal neurons to cardiac input, J. Neurophysiol., 58 (1987) 1149-1167. Blair, R.W. and Foreman, R.D., Activation of feline spinal neurons by potentiated ventricular contractions and other mechanical cardiac stimuli, J. Physiol. (Lond.), 404 (1988) 649-667. Blair, R.W., Ammons, W.S. and Foreman, R.D., Responses of thoracic spinothalamic and spinoreticular cells to coronary artery occlusion, J. Neurophysiol., 51 (1984) 636-648. Blair, R.W., Weber, R.N. and Foreman, R.D., Characteristics of primate spinothalamic tract neurons receiving viscerosomatic convergent inputs in T3-T5 segments, J. Neurophysiol., 46 (1981) 797-811. Blair, R.W., Weber, R.N. and Foreman, R.D., Responses
of thoracic spinothalamie neurons to intracardiac injections of bradykinin in the monkey, Circ. Res., 51 (1982) 83-94. 61 Blair, R.W., Weber, R.N. and Foreman, R.D., Responses of thoracic spinoreticular and spinothalamic cells to intracardiac bradykinin, Am. J. Physiol., 246 (1984) H500H507. 62 Block, A.J., Feinberg, H., Herba~ynska-Ccdro, K. and Vane, J.R., Anoxia and induced release of prostaflandins in rabbit isolated hearts, Circ. Res., 36 (1975) 34-42. 63 Bloomfield, A.L. and Polland, W.S., Experimental referred pain from the gastro-intestinal tract. II. Stomach, duodenum and colon, Jo Cliff. Invest., 10 (1931) 453-473. 64 Blumberg, B., Haupt, P., J~nig, W. and KShler, W., Encoding of visceral noxious stimuli in the discharge patterns of visceral afferent fibres from the colon, Pfliigers Arch., 398 (1983) 33-40. 65 Boley, S.J., Agrawal, G.P., Warren, A.R., Veith, F.J., Levowitz, B.S., ]reiber, W., Dougherty, J., Schwartz, S.S. and Gfiedman, M.L., Pathophysiologic effects of bowel distention on intestinal blood flow, Am. J. Surg., 117 (1969) 228-234. 66 Boyden, E.A. and Rifler, L.G., Localization of pain accompanying faradiz~tion of stomach and duodenum in healthy individuals, J. Clin. Invest., 13 (1934) 833-851. 67 Brasch, H. and Zetler, G., Caerulein and morphine in a model of visceral pain: effects on the hypotensive reponse to renal pelvis distension in the rat, Naunyn-Schmiedeberg's Arch. Pharmacol., 319 (1982) 161-167. 68 Brennan, T.J., Oh, U.T,, Girardot, M.-N., Ammons, W.S. and Foreman, R.D., Inhibition of cardiopulmonary input to thoracic spinothalamic tract cells by stimulation of the subcoeruleus-parabrachial region in the primate, J. Auton. Nerv, Syst., 18 (1987) 61-72. 69 Brennan, T.J., Oh, U.T., Hobbs, S.F., Garrison, D.W. and Foreman, R.D., Urinary bladder and hindlimb afferent input inhibits activity of primate T2-T5 spinothalamic tract neurons, J. Ncurophysiol., 61 (1989) 573-588. 70 Brown, A.M., Excitation of afferent cardiac sympathetic nerve fibres during myocardial ischemia, J. Physiol. (Lond.), 190 (1967) 35-53. 71 Brown, A.M. and Malliani, A., Spinal sympathetic reflexes initiated by coronary receptors, J. Physiol. (Lond.), 212 (1971) 685-705. 71a Brown, S.T., Campbell, D. and Kurtz, A., Characteristics of labor pain at two stages of cervical dilation, Pain, 38 (1989) 289-295. 72 Burch, G.E. and DePasquale, N.P., Bradykinin, digital blood flow, and the arteriovenous anastamoses, Circ. Res., 10 (1962) 105-115. 73 Cadden, S.W. and blorrison, J.F.B., The effects of visceral distension on the activities of lumbar dorsal horn neutones in the rat, J. Physiol. (Lond.), 350 (1984) 71P. 74 Calaresu, F.R., Stella, A. and Zanchetti, A., Haemodynamic responses and renin release during stimulation of afferent renal nerve in the cat, J. Physiol. (Lond.), 255 (1976) 687-700. 75 Calaresu, F.R., Tobey, J.C., Heidemann, S.R. and Weaver,
221 L., Splenic and ren~! sympathetic responses to stimulation of splenic receptors in cats, Am. J. Physiol., 247 (1984) R856-R865. 76 Calvino, B., Villanueva. L. and Le Bars, D., The heterotopic effects of visceral pain: behavioural and electrophysiological approaches in the rat, Pain~ 20 (1984) 261-271. 77 Cannon, B., A method of stimulating autonomic nerves in the unanesthetized cat with observation on the motor and sensory effects, Am. J. Physiol., 105 (1933) 366-372. 78 Capps, J.A. and Coleman, G.H., Experimental observation on the localization of the pain sense in the parietal and diaphragmatic peritoneum, Arch. Intern. Med., 30 (1922) 778-789. 79 Caprilli, R., Capurso, L. e Paolu~, P., Studio de~ dolore da distensione delrileo e del crasso nelruomo, Arch. Ital. Mal. Appar. Dig., 34 (1967) 268-278. 80 Carlson, A.J. and Braafladt, L.H., Contributions to the physiology of the stomach, Am. J. Physiol., 36 (1915) 153-170. 81 Carlson, A.J. and Luckhardt, A.B., Studies on the visceral sensory nervous system. V. Cardiac and vasomotor reflexes induced by visceral stimulation in amphibia and reptilia, Am. J. Physiol., 55 (1921) 31-52. 82 Carstens, E. and Yokota, T., Viscerosomatic convergence and responses to intestinal distension of neurons at the junction of midbrain and posterior thalamus in the cat, Exp. Neurol., 70 (1980) 392-402. 83 Ca.~ati, R., Lombardi, F. and Malliani, A., Afferent sympataet~c unmyelinated fibres g~th left ventricular endings in cats, J. Physiol. (Lond.), 292 (1979) 135-148. 84 Cassidy, S.S., Ashton, J.H., Wead, W.B., Kaufman, M.P., Monsereenusorn, Y. and Whiteside, J.A., Reflex cardiovascular responses caused by stimulation of pulmonary C-fibers with capsaicin in dogs, J. Appl. Physiol., 60 (1986) 949-958. 85 Cechetto, D.F. and Saper, C.B., Evidence for a viscerotopic sensory representation in the cortex and thalamus in the rat, J. Comp. Neurol., 262 (1987) 27-45. 86 Cervero, F., Noxious intensities of visceral stimulation art~ required to activate viscerosomatic multireceptive neurons in the thoracic spinal cord of the cat, Brain Res., 240 (1982) 350-352. 87 Cervero, F., Afferent activity evoked by natural stimulation of the bifiary system in the ferret, Pain, 13 (1982) 137-151. 88 Cervero, F., Supraspinal connections of neurones in the thoracic spinal cord of the cat: ascending projections and effects of descending impulses, Brain Res., 275 (1983) 251-261. 89 Cervero, F., Somatic and visceral inputs to the thoracic spinal cord of the cat: effects of noxious stimulation of the biliary system, J. Physiol. (Lond.), 337 (1983) 51-67. 90 Cervero, F., Fine afferent fibres from viscera and visceral pain: anatomy and physiology of viscero-somatic convergence. In: R.F. Sclunidt, H.G. Schaible and C. Vahle-Hinz (Eds.), Fine Afferent Nerve Fibers and Pain, VCH, Weinheim, 1987, pp. 322-331. 91 Cervero, F. and Connell, L.A., Distribution of somatic
and visceral primary afferent fibres within the thoracic spinal cord o¢ ~he cat, J. Comp. Neurol., 230 (1984) 88-98. 92 Cervero, F., Connell, L.A. and Lawson, S.N., Somatic and visceral primary afferents in the lower thoracic dorsal root ganglia of the cat, J. Comp. Neurol., 228 (1984) 422-431. 93 Cervero, F. and Iggo, A., Natural stimulation of urinary bladder afferents does not affect transmission through hmbosacral spinocervical tract neurones in the cat, Brain Res., 156 (1978) 375-379. 94 Cetvero, F. and Lumb, B.M., Bilaterai inputs and supraspinal control of viscerosomatic neurones in the lower thoracic cord of the cat, J. Physiol. (Lond.), 403 (1988) 221-237. 95 Cervero, F., Lumb, B.M. and Tattersall, J.E.H., Supraspihal loops that mediate visceral inputs to thoracic spina: cord neurones in the cat: involvement of descending pathways from raphe and reticular formation, Neurosci. Lett., 56 (1985) 189-194. 96 Cervero, F. and Tattersall, J.E.H., Cutaneous receptive fields of somatic and viscerosomatic neurones in the thoracic spinal cord of the cat, J. Comp. Neurol., 237 t l o ~ -~'~ _3~t2 97 Cervero, F. and Tattersall, J.E.H., Somatic and visceral sensory integration in the thoracic spinal cord. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 189-206. 98 Cervero, F. and T~ttersall, J.E.H., Somatic and visceral inputs to the thoracic spinal cord of the cat: marginal zone (lamina I) of the dorsal horn, J. Physiol. (Lond.), 388 (1987) 383-395. 99 Chandler, M.J., Garrison, D.W., Brennan, T.J. and Foreman, R.D., Effects of chemical and electrical stimulation of the midbrain on feline T2-T6 spinoreticular and spinal cell activity evoked by cardiopulmonary afferent input, Brain Res., 496 (1989) 148-164. 100 Chapman, C.D, Ammons, W.S. and Foreman, R.D., Raph¢ magnus inhibition of feline T1-T4 spinoreticular tract cell responses to visceral and somatic inputs, .I. Neurophysio,~., 53 (1985) 773-785. 101 Chapman, W.P., Herrera, R. and Jones, C.M., A comparison of pain produced experimentally in lower esophagus, common bile duct, and upper small intestine with pain experienced by patients with diseases of biliary tract and pancreas, Surg. Gynecol. Obstet., 89 (1949) 573-582. 102 Chapman, W.P. and Jones, C.M., Variations in cutaneous and visceral pain sensitivity in normal subjects, J. Chn. Invest., 23 (1944) 81-91. 103 Ciriello, J. and Calaresu, F.R., Central projections of afferent renal fibers in the rat: an anterograde transport study of horseradish peroxidase, J. Auton. Nerv. Syst., 8 (1983) 273-285. 104 Clark, S.J. and Smith, T.W., Opiate-induced inhibition of the visceral distension reflex by peripheral and central mechanisms, Naunyn-Schmiedeberg's Arch. Pharmacol., 330 (1985) 179-183. 103 Clelland, J.G.P. and Tait, J., Nervous connections of the X4. j v , , , i
,,pau,,,,-
,..,
.
222 mammalian spleen, including an account of certain visceromotor and other abdominal reflexes, Quart. J. Exp. Physiol., 17 (1927) 179-204. 106 Clifton, G.L., Coggeshall, R.E., Vance, W.H. and Willis, W.D., Receptive fields of unmyelinated ventral root afferent fibres in the cat, J. Physiol. (Lond.), 256 (1976) 573600. 107 Clifton, G.L., Vance, W.H., Applebaum, K.L., Coggeshall, R.E. m~d Willis, W.D., Responses of unmyelmated afferents in the mammalian ventral root, Brain Res., 82 (1974) 163-167. 108 Coffman, J.D., The effect of aspirin on pain and hand blood flow responses to intra-arterial injection of bradykinin, Clin. Pharmacol. Ther., 7 (1966) 26-37. 109 Coggeshall, R.E. and Ito, H., Sensory fibres in ventral roots L7 ar.~ $1 in the cat, J. Physiol. (Lond.), 267 (1977) 215-235. 110 Cohen, H., Visceral pain, Lancet, ii (1947) 6487-6489. 111 Colburn, R.W., Coombs, D.W., Degnen, C.C. and Rogers, L.L., Mechanical visceral pain model: chronic intermittent intestinal distension in the rat, Physiol. Behav., 45 (1989) 191-197. 112 Coombs, D.W., Rogers, L.L., Raye, K.N. and Addis, M., Dose-response of intrathecal clonidine in the rat mechanical visceral pain model, Neurosci. Abst., 14 (1988) 175. 113 Cormia, F.E. and Dougherty, J.W., Proteolytic activity in development of pain and itching, J. Invest. Dermatol., 35 (1960) 21-26. 114 Craig, A.D. and Mense, S., The distribution of afferent fibers from the gastrocnemius-soleus muscle in the dorsal horn of the cat as revealed by the transport of horseradish peroxidase, Neurosci. Lett., 41 (1983) 233-238. 115 Cross, B.A., The motility and reactivity of the oestrogenized rabbit uterus in vivo; with comparative observations on milk ejection, J. Endocrinol., 16 (1958) 237-260. 116 Crousillat. J., Ranieri, F., Mei, N. et Aubert, M., Effets de la stimulation des fibres et des mt~cia,'mor6cepteurs splanehnique ~ur l'acfivit6 unitaJrc du co~'tex ~,omatique, Pfltigers Arch., 348 (1974) 127-137. 117 Crowley, R.T., Reflex modification of respiration by intestinal distentionl Am. J. Physiol., 133 (1941) 253-254. 118 Csendes, A. and Sepulveda, A., lntraluminal gallbladder pressure measurements in patients with chronic or acute cholecystitis, Am. J. Surg., 139 (1980) 383-384. 119 Cuilen, M.L. and Reese, H.L., Myocardial circulatory changes measured by clearance of Na 2'* - effect of common duct distension on myocardial circulation, J. Appl. Physiol., 5 (1952) 281-284. 120 Cunningham D.J.C., Guttmann, L., Whitteridge, D. and Wyndham, C.L., Cardiovascular response to bladder distension in paraplegic patients, J. Physiol. (Lond.), 121 (1953) 581-592. 121 Dalsgaard, C.-J. and Lundberg, J.M, Evidence for a spinal afferent innervation of the guinea pig lower respiratory tract as stud~ed by the horseradish peroxidase technique, Neurosci. Lett., 45 (1984) 117-122. 122 Dalsgaard, C.-J. and Ygge, J., Separate populations of
primary sensory neurons project to the splanchnic nerve and thoracic spinal nerve rami of the rat. A fluorescent double-labelling study, Med. Biol., 63 (1985) 88-91. 123 Danzebrink, R.M., and Gebhart, G.F., Visceral nociception: inhibition by spinal a2-adrenoceptors, Neurosci. Abst., 14 (1988) 851. 124 Davis, K.D. and Dostrovsky, J.O., Activation of trigeminal brain-stem nociceptive neurons by dural artery stimulation, Pain, 25 (1986) 395-401. 125 Davis, L., The pathway for visceral afferent impulses within the spinal cord, Am. J. Physiol., 59 (1922) 381-393. 126 Davis, L., Hart., J.T. and Crain, R.C., The pathway for viscer-d afferent impulses within the spinal cord, Surg. Gyn~col. Obstet., 48 (1929) 647-651. 127 Davis, L. and Pollock, L.J., The peripheral pathway for painful sensatior.s, Arch. Neuro!. Psychiat., 24 (1930) 883-898. 128 Davis, L., Pollock:. L.J. and Stone, T.T., Visceral pain, Surg. Gynecol. O~stet., 55 (1932) 418-427. 129 DeGroat, W.C., lahibition and excitation of sacral parasympathetic neurons by visceral and cutaneous stimuli in the cat, Brain Res., 33 (1971) 499-503. 130 DeGroat, W.C., Spinal cord projections and neuropeptides in visceral afferent neurons. In: F. Cerver¢ and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 165-187. 131 DeGroat, W.C., Neuropeptides in pelvic afferent pathways, Experientia, 43 (1987) 801-813. 132 DeGroat, W.C., Booth, A.M., Milne, R.J. and Roppolo, J.R., Parasympathetic preganglionic neurons in the sacral spinal cord, J. Auton. Nerv. Syst., 5 (1982) 23-43. 133 DeGroat, W.C., Nadelhaft, I., Milne, R.J., Booth, A.M.. Morgan, C. and Thor, K., Organization of the sacral parasyrogathetic reflex pathways to the urinary bladder and large intestine, J. Auton. Nerv. Syst., 3 (1981) 135-160. 133a DeLeo, J.A., Colburn, R.W., Coombs, D.W. and Ellis, M.A., The differentiation of NSAIDS and prostaglandin action using a mechanical visceral pain model in the rat, Pharmaeol. Biochem. Behav., 33 (1989) 253-255. 134 Denny-Brown, D. and Robe,'tson, E.G., On the physiology of micturition, Brain, 56 (1933) 149-190. 135 Deraedt, R., Jouquey, S., Deleval6e, F. and Flahaut, M., Release of prostaglandins E and F in an algogenic reaction and its inhibition, Eur. J. Pharmacol., 61 (1980) 17-24. 136 Devroede, G., Vobecky, S., Masse, S., Arhan, P., Leger, C., Duguay, C. and Hemond, M., Ischemic fecal incontinence and rectal angina, Gastroenterology, 83 (1982) 970980. 137 Dickerson, G.D., Engle. R.J., Guzman, F., Rodgers, D.W. and Lira, R.K.S., The intraperitoneal bradykinin-evoked pain (BK-EP) test for analgesia, Life Sei., 4 (1965) 20632069. 138 Dockray, G.J. and Sharkey, K.A., Neurochemistry of viscer~ afferent neurons, in: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 133-148.
223 138a Doerffler-Melly, J. and Neuhuber, W.L., Rectospinai neurons: evidence for a direct projeca~a from the enteric to the central nervous system in the rat, Neurosci. Lett., 92 (1988) 121-125. 139 Donovan, M.K., Wyss, J.M. and Wintemitz, S.R., Localization of renal sensory neurons using the fluorescent dye technique, Brain Res., 259 (1983) 119-122. 140 Doran, F.S.A., The sites to which pain is referred from the con~non bile duct in man and its impfication for the theory of referred pain, Br. J. Surg., 54 (1967) 599-606. 141 Doran, F.S.A. and Ratcliffe, A.H., The physiological mechanism of referred shoulder-tip pain, Brain, 77 (1954) 427-434. 142 Downie, J.W., Champion, J.A. and Nance, D.M., A quantitative analysis of the afferent and extrinsic efferent innervation of specific regions of the bladder and urethra in the cat, Brain Res. Bull., 12 (1984) 735-740. 143 Downman, C.B.B., Cerebral destination of splanchnic afferent impulses, J. Physiol. (Lond.), 113 (1951) 434-441. 144 Downman, C.B.B., Skeletal muscle reflexes of splanchnic and intercostal nerve origin in acute spinal and decerebrate cats, J. Neurophysiol., 18 (1955) 217-235. 145 Downman, C.B.B. and Evans, M.H., The distribution of splanclmic afferents in the spinal cord of cat, J. Physiol. ~Lond.), 137 (1957) 66-79. 146 Downman, C.B.B. and McSwiney, B.A., Reflexes elicited by visceral stimulation in the acute spinal animal, J. Physiol. (Lond.), 105 (1946) 80-94. 147 Downman, C.B.B., McSwiney, B.A. and Vass, C.C.N., Sensitivity of the small intestine, J. Physiol. (Lond.), 107 (1948) 97-106. 148 Dray, A. and Nunan, L., Opioid inhibition of reflex urinary bladder contractions: dissociation of supraspinal and spinal mechanisms, Brain Res., 337 (1985) 142-145. 149 Dworken, H.J., Biel, F.J. and Machella, T.E., Supradiaphragmatic reference of pait~ ¢ro~ :he ~olo-, Gastroen,,~rology, 22 (!952) 222--229. 150 Edgeworth, F.H., On a large-fibred sensory supply of the thoracic and abdominal viscera, J. Physiol. (Lond.), 13 (1892) 260-271. 151 Elam, M., Thoren, P. and Svensson, T.H., Locus coeruleus neurons and sympathetic nerves: activation by visceral afferents, Brain Res., 375 (1986) 117-125. 152 Ellison, J.P. and Clark, G.M., Relxograde axonal transport of horseradish peroxidase in peripheral autonomic nerves, J. Comp. Neurol., 161 (1974)~03-114. 153 EIfvin, L.G. and Dalsgaard, C.J., Retrograde axonal transport of horseradish peroxidase in afferent fibers of the inferior mesenteric ganglion of the guinea pig, Brain Res., 126 (1977) 149-153. 154 Evans, M.H. and McPherson, A., The effects of distension of the bladder on somatic reflexes in the cat, J. Physiol. (Lond.), 146 (1959) 448-458. 155 Farthing, M.J.G. and Lennard-Jones, J.E., Sensibility of the rectum to distension and the anorectal distension reflex in ulcerative colitis, Gut, 19 (1978) 64-69. 156 Felder, R.B. and Thames, M.D., Responses to activation
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
of cardiac sympathetic afferents with epicardial bradykinin, Am. J. Physiol., 242 (1982) 148-153. Felder, R.B. and Thames, M.D., The cardiocardiac sympathetic reflex during coronary occlusion in anesthetized dogs, Circ. Res., 48 (1981) 685-692. Fields, H.L., Meyer, G.A. and Partridge, Jr., L.D., Convergence of visceral and somatic input onto spinal neurons, Exp. Neurol., 26 (1970) 36-52. Fie~ds, I-I.L., Partridge, Jr., L.D. and Winter, D.L., Somatic and visceral receptive field properties of fibers in ventral quadrant white matter of the cat spinal cord, J. Neurophysiol., 33 (1970) 827-837. Fields, H.L. and Winter, D.L., Somatovisceral pathway: rapidly conducting fibers in the spinal cord, Science, 167 (1970) 1729-1730. Flower, R.J., Moncada, S. and Vane, J.R., Analgesic-antipyretics and anti-inflammatory agents and drugs employed in the treatment of gout. In" A.G. Gilman, L.S. Goodman, T.W. Rall and F. Murad (Eds.), Goodman and Gilman's Pharmacological Basis of Therapeutics, 7th edition, MacMillan, New York, 1985, pp. 674-715. Floyd, K., Hick, V.E., Koley, J. and Morrison, J.F.B., Effects of bradykinin mediated by autonomic efferent nerves, Quart. J. Exp. Physiol., 62 (1977) 11-17. Floyd, K., Hick, V.E., Koley, J. and Morrison, J.F.B., The effects of bradykinin on afferent units in intra-abdominal sympathetic nerve trunks, Quart. J. Exp. Physiol., 62 (1977) 19-25. Floyd, K., Hick, V.E. and Morrison, J.F.B., Mechanosensitive afferent units in the hypogastric nerve of the cat, J. Physiol. (Lond.), 259 (1976) 457-471. Floyd, K., Koley, J. and Morrison, J.F.B., Afferent discharges in the sacral ventral roots of cats, J. Physiol. (Lond.), 259 (1976) 37-38. Floyd, K. and Morrison, J.F.B., Splancbnic mechanoreceptors in the dog, Quart. J. Fxp. Physiol., 59 (1974) 361-366. Ford, G.T., Grant, D.A,, RJdeout, K.S., Davidson, J.S. and Wlfitelow, W.A., Inhibition of breathing associated with gall bladder stimulation in dogs, J. Appl. Physiol., 65 (1988) 72-79. Foreman, R.D., Viscerosomatic convergence onto spinal neurons responding to afferent fibers located in the inferior cardiac nerve, Brain Res., 137 (1977) 164-168. Foreman, R.D., Blair, R.W. and Weber, R.N., Vi~cerosomatic convergence onto T2-T4 spinoreticular, spinoreticular-spinothalamic, and spinothalamic tract neurons in the cat, Exp. Neurol., 85 (1984) 597-619. Foreman, R.D., Hancock, M.B. and Willis, W.D., Responses of spinothalamic tract cells in the thoracic spinal cord of the monkey to cutaneous and visceral inputs, Pain, 11 (1981) 149-162. Foreman, R.D. and Ohata, C.A., Effects of coronary artery occlusion on thoracic spinal neurons receiving viscerosomatic inputs, Am. J. Physiol., 238 (1980) H667H674. Foreman, R.D. and Weber, R.N., Responses from neurons
224 of the primate spinothalamic tract to electrical stimulation of afferents from the cardiopulmonary region and somatic structures, Brain Res., 186 (1980) 464-468. 173 Fox, R.H., Goldsmith, R., Kidd, D.J. and Lewis, G.P., Bradykinin as a vasodilator in man, J. Physiol. (Lond.), 157 (1961) 589-602. 174 Frank, M.H., Cardiovascular chemoreflexes from the perfused innervated ileum of the cat, Am. J. Physiol., 228 (1975) 944-953. 175 Fukuda, H. and Fukai, K., Postural change and straining induced by distension of the rectum, vagina and urinary bladder of decerebrate dogs, Brain Res., 380 (1986) 276286. 176 Fukuda, H. and Fukai, K., Ascending and descending pathways of reflex straining in the dog, Jpn. J. Physiol., 36 (19Rfi) 905-920. 177 Fukuda, H., Fukai, K., Yamane, M. and Okada, H., Pontine reticular unit responses to pelvic nerve and colonic mechanical stimulation in the dog, Brain Res., 207 (1981) 59-71. 178 Fukuda, H. and Koga, T., Midbrain stimulation inhibits the micturition, defecation and rhythmic straining reflexes elicited by activation of sacral vescical and rectal afferents in the dog, Brain Res., submitted. 179 Gaensler, E.A., Quantitative determination of the visceral pain threshold in man: charactenst|cs of visceral pain, effect of inflammation and analgesics on the threshold, and relationship of analgesia to visceral spasm, J. Clin. Invest., 30 (1951) 406-420. 180 Garrison, D.W., Chandler, M.J. and Foreman, R.D., Viscerosomatic convergence onto T2-T5 spinal cord dorsal horn cells from distal esophagus, heart and somatic fields in cat, Neurosci. Abst., 13 (1987) 582. 181 Garrison, D.W., Chandler, M.J. al~d Foreman, R.D, Responses of T2-T7 dorsal horn cells to distension of in. flamed and normal distal esophagus in cat, Neurosci. Abst., 14 (1Q88) 562. 182 Gernandt, B. and Zotterman, Y., Intestinal pain: an electrophysiological investigation on mesenteric nerves, Acta Physiol. Scand., 12 (1946) 56-72. 183 Giesler, Jr., G.J. and Liebeskind, .i.C., Ie~hibition of visceral pain by electrical stimulation of the periaqueductal gray matter, Pain, 2 (1976) 43-48. 184 Gilbert, N.C., Fenn, G.K. and LeRoy, G.V., The effect of distension of abdominal viscera on the coronary blood flow and on angina pectoris, JAMA, 115 (1940) 1962-1967. 185 Gilmore, J.P. and Tomomatsu, E., Renal mechanoreceptors in nonhuman primates, Am. J. Physiol., 248 (1985) R202-R207. 186 Giuliani, S., Maggi, C.A. and Meli, A., Capsaicin-sensitive afferents in the rat urinary bladder activate a spinal sympathetic cardiovascular reflex, Naunyn-Schmiedeberg's Arch. Fharmacoi., 338 (1988) 411-416. 1o7 Gokin, A.P., Synaptic activation of interneurons in the thoracic ~pinal cord by cutaneous, muscle and visceral afferents, Neurophysiology (Kiev), 2 (1970) 563-572.
188 Gokin, A.-P., Kostyuk, P.-G. and Preobrazhensky, N.-N., Neuronal mechanisms of interactions of high-threshold visceral and somatic afferent influences in spinal cord and medulla, J. Physiol. (Paris), 73 (1977) 319-333. 189 Goligher, J.C. and Hughes, E.S.R., Sensibility of the rectum and colon: its role in the mechanism of anal continence, Lancet, i-ii (1951) 543-548. 190 Gorman, A.J. and Zucker, I.H., Renal nerve and blood pressure responses to stimulation of cardiac receptors in dogs and cats by bradykinin, Basic Res. Cardiol., 79 (1984) 142-154. 191 Goshgarian, H.G. and Roubal, P.J., Origin and distribution of phrenic primary afferent nerve fibers in the spinal cord of the adt,,lt rat, Exp. Neurol., 92 (1986) 624-638. 191a Gottfried, S B. and DiMarco, A.F., Effect of intestinal afferent stimulation on pattern of respiratory muscle activation, J. Appl. Physiol., 66 (1989) 1455-1461. 192 Guilbaud, G., Benelli, G. and Besson, J.M., Responses of thoracic dorsal horn interneurons to cutaneous stimulation and to the administration of algogenic substances into the mesenteric artery in the spinal cat, Brain Res., 124 (1977) 437-448. 192a Gutterman, D.D., Pardubsky, P.D. and Gebhart, G.F., Attenuation of afferent spinal neuronal responses to successive coronary occlusions may contribute to silent ischemia, Circulation, 80 (1989) 552. 193 Guttmann, L. and Whitteridge, D., Effects of bladder distension on autonomic mechanisms after spinal cord injuries, Brain, 70 (1947) 361-404. 194 Guzman, F., Braun, C. and I,im, R.K.S., Visceral pain and the pseudaffective response to intra-arterial injection of bradykinin and other algesic agents, Arch. Int. Pharmacodyn., 136 (1962) 353-384. 195 Guzman, F., Braun, C., Lira, R.K.S., Potter, G.D. and Rodgers, D.W., Narcotic and non-narcotic analgesics wlfich block visceral pain evoked by the intraarterial injection of bradykinin and other algesic agen,,s, Arch. int. Pharmacodyn., 149 (1964) 571-588. 196 Gyires, K. and Totma, Z., The use of the writhing test in mice for screening different types of analgesia, Arch. Int. Pharmacodyn., 267 (1984) 131-140. 197 Hiibler, H.-L, A novel type of unmyelinated chemosensitire nociceptors in the acutely inflamed urinary bladder, Agents Actions, 25 (1988) 219-221. 198 Hiibler, H.-J., J~inig, W. and Koltzenberg, M., Dichotomiring unmyelinated afferents supplying pelvic viscera and perineum are rare in sacral segments of the cat, Neurosci. Lett., 94 (1988) 119-124. 199 Hancock, M.B., Foreman, R.D. and Willis, W.D., Convergence of visceral and cutaneous input onto spinothalamic tract cells in the thoracic spinal cord of the cat, Exp. Neurol., 47 (1975) 240-248. 200 Hancock, M.B., Rigamonti, D.D. and Bryan, R.N., Convergence in the lumbar spinal cord of pathways activat~,~ by splanchnic nerve and hind limb cutaneous nerve stimulation, Exp. Neurol., 38 (1973) 337-348.
225 201 Hanson, K.M., Hemodynamic effects of distension of the :log small intestine, Am. J. Physiol., 225 (1973) 456-460. 202 Hanson, K.M. and Moore, F.T., Pressure-volume relationships and bloodflow in the distended colon, Am. J. Physiol., 217 (1969) 35-39. 203 Hardy, J.D., Wolf, H.G. and Good¢ll, H., Pain Sensations and Reactions, Williams and Wilkins, Baltimore, MD, 1952. 204 Hashimoto, K., Hirose, M., Furakawa, S., Hayakawa, H. and Kimura, E., Changes in hcmodynamics and bradykinin concentrations in coronary sinus blood in experimental coronary artery occlusion, Jpn. Heart J., 18 (1977) 679689. 205 Haupt, P., J~nig, W. and K61fler, W., Response pattern of visceral afferent fibres, supplying the colon, upon chemical and mechanical stimuli, Pfliigers Arch., 398 (1983) 41-47. 206 Hazarika, N.H., Coote, J. and Downman, C.B.B., Gastrointestinal dorsal root viscerotomes in the cat, J. Neurophysiol., 27 (1964) 107-116. 207 Head, H., On disturbances of sensation, with special reference to the pain of visceral diseases, Brain, 16 (1893) 1-133. 208 Hvndershot, L.C. and Forsaith, J., Antagonism of the frequency of phenylquinone-induced writhing in the mouse by weak analgesics and nonanalgesics, J. Pharmacol. Exp. Ther., 125 (1959) 237-240. 209 Hertz, A.F., The sensibility of the alimentary tract in health and disease, Lancet, i (1911) 1051-1056; 11191124; 1187-1193. 210 Hino, O., Kanafusa, K. and Tsunekawa, K., Quantitative histological study of spinal afferent innervation on the ventral surface of the cat stomach by horseradish peroxidase (HRP) method, Experientia, 35 (1979) 379-380. 211 Hinsey, J.C. and Phillips, R.A., Observations upon diaphragmatic sensation, J. Ncurophysiol., 3 (1940) 175-181. 212 Hedge, G.B. and Messer, A.L., The electrocardiogram in biliary tract disease and during experimental biliary distension: clinical observations on 26 patients, Surg. Gynecol. Obstet., 86 (1948) 617-626. 213 Holdstock, D.J., Misiewicz, J.J. and Waller, S.L., Observations on the mechanism of abdominal pain, Gut, 10 (1969) 19-31. 214 Holt, I.L., Coulombe, P.R. and Kneupfer, M.M., Role of nucleus raphe magnus (NRM) in modulation of renal afferent input, Neurosci. Abst., 14 (1988) 174. 215 Honda, C.N., Visceral and somatic afferent convergence onto neurons near the central canal in the sacral spinal cord of the cat, J. Ncurophysiol., 53 (1985) 1059-1078. 216 Honda, C.N., Rethelyi, M. and Petrusz, P., Preferential immunohistochemical localization of vasoactive intestinal polypeptide (V!P) in the sacral spinal cord of the cat: light and electron microscopic observations, J. Neurosci., 3 (1983) 2183-2196. 217 Hornby, J.B. and Rose, J.D., Responses of caudal brain-
stem neurons to vaginal and somatosensory stimulation in the rat and evidence of genital-nociceptive interactions, Exp. Neurol., 51 (1976) 363-376. 218 Horton, E.W.. The role of bradykinin in the periFh~.ral nervous system, Ann. NY Acad. Sci., 104 0963) 250-257. 219 Hulsebosch, C.E. and Coggeshall, R.E., An analysi~ of the axe, populations in the nerves to the pelvic viscera in ',he rat, J. Comp. Neurol., 211 (1982) 1-10. 220 lwamoto, G.A., Waldrop, T.G., Longhurst, J.C. and Ordway, G.A., Localization of the cells of origin for primary afferent fibers supplying the gall bladder of the cat, Exp. Neuroi., 84 (1984) 709-714. 221 Jain, S.K., Subramanian, S., Julka, D.B. and Guz, A., Search for evidence of lung chemoreflexes in man: study of respiratory and circulatory effects of phenyldiguanide and Iobeline, Clin. Sci., 46 (1972) 163-177. 222 Jiinig, W. and Koltzenberg, M., The neural basis of consciously perceived sensations from the gut, Gut, in press. 223 J~inig, W. and McLachlan~ EM., O r d i n a t i o n of lumbar spinal outflow to distal colon and pelvic organs, Physiol. Rev., 67 (1987) 1332-1404. 224 Jiinig, W. and Morrison, J.F.B., Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 87-114. 224a Janssen, B.J.A., Van Essen, H., Struyker Boudier, H.A.J. and Smits, J.F.M., Hemodynamic effects of activation of renal and mesenteric sensory nerves in rats, Am. J. Physiol., 257 (1989) R29-R36. 225 ]avert, C.T. and Hardy, J.D., Measurement of pain intensity in labor and its physiologic, neurologic and pharmacologic implications, Am. J. Obstet. Gynecol., 60 (1950) 552-563. 226 Jeanningros, R., Modulation of lateral hypothalamus single unit activity by gastric and intestinal disten~ion, J. Auton. Nerv. Syst., !1 (1984) !-11. 227 Jensen, F.M., Madsen, J.B., Ringsted, C.V. and Christensen, A., Intestinal distension test, a method for evaluating intermittant visceral pain in the rabbit, Life Sci., 43 (1988) 747-754. 228 Iohansson, B. and Langston, J.B., Reflex influence of mesenteric afferents on renal, intestinal and muscle blood flow and on intestinal motility, Acta Physiol. Scand., 61 (1964) 400-412. 229 Jones, C~4., Pain from. the digestive tract, Prec. Ass. Res. Nerv. Ment. Dis., 23 (1943) 274-289. 230 Jones, C.M. and Pierce, F.D., Mechanism and reference of pain from the lower intestinal tract, Trans. Ass. Am. Physcns, 46 (1931) 311-312. 231 Kachelhoffer, J., Pousse, A., Marescaux, J., Iturizaga, M. and Grenier, J.F., Effects of motility and luminal distension on dog small intestine hemodynamics, Eur. Surg. Res., 10 (1978) 184-193.
226 232 Kamikawa, K., Tatsua, S., Koshino, K. and Kuru, M., Analysis of lateral column units related to vesical reflexes, Exp. Neurol., 6 (1962) 271-284. 233 Kanui, T.I., Responses of spinal cord neurones to noxious and non-noxious stimulation of the skin and testicle of the rat, Neurosci. Lett., 58 (1985) 315-319. 234 Katz, L.N., Mayne, W. and Weinstein, W., Cardiac pain presence of pain fibers in the nerve plexus surrounding the coronary vessels, Arch. Intern. Med., 55 (1935) 760-772. 235 Kawatani, M., Nagel, J. and DeGroat, W.C., Identification of neuropeptides in pelvic and pudendal nerve afferent pathways to the sacral spinal cord of the cat, J. Comp. Neurol., 249 (1986) 117-132. 236 Kend~,Jl, G.P.N., Visceral pain, Br. J. Surg., 72 (1985) 4-5. 237 Khayutin, V.M., B~az, L.A., L u ~ h k o v a , E.V., Sonina, R.S. and Chernilovs::ay~, P.E.. Chemosensitive spinal afferents: thresholds of specific and nociceptive reflexes as compared with thresholds of excitation for receptors and axons. In: A. Iggo and O.B. llyinski (Eds.), Somatosensory and Visceral Receptor Mechanisms. Prog. Brain Res., Vol. 43, Elsevier, Amsterdam, 1974, pp. 293-306. 238 Kimura, E., Hashimoto, K., Furukawa, S. and Hayakawa, H., Changes in bradykinin level in coronary sinus blood after the experimental occlusion of a coronary artery, Am. Heart J., 85 (1973) 635-647. 239 King, B.F. and Szurszewski, J.H., Mechanoreceptor pathways from the distal colon to the autonomic nervous system in the guinea pig, J. Physiol. (Lond.), 350 (1984) 93-107. 240 Kingham, J.C.G. and Dawson, A.M., Origin of chronic right upper quadrant pain, Gut, 26 (1985) 783-788. 241 Kinsella, V.J., Sensibility in the abdomen, Br. J. Surg., 27 (1940) 449-463. 242 Klein, C.M. and Burden, H.W., Anatomical localization of afferent and postganglionic sympathetic neurons innervating the rat ovary, Neurosci. Lett., 85 (1988) 217-222. 243 Knuepfer, M.M. and Schramm, L.P., Properties of re. nobulbar afferent fibers in rats, Am. J. Physiol., 248 (1985) Rl13-Rl19. 244 Knuepfer, M.M. and Schramm, L.P., The conduction velocities and spinal projections of single renal afferent fibers in the rat, Brain Res., 435 (1987) 167-173. 245 Knuepfer, M.M., Akeyson, E.W. and Schramm, L.P., Spinal projections of renal afferent nerves in the rat, Brain Res., 446 (1988) 17-25. 246 Koltzenburg, M. and McMahon, S.B., Plasma extravasation in the rat urinary bladder following mechanical, electrical and chemical stimuli: evidence for a new population of chemosensitive primary sensory afferents, Neurosci. Lett., 72 (1936) 352-356. 247 Komisaruk, B.R. and Whipple, B., Vaginal stimulationproduced analgesia in rats and ,vomen, Ann. NY A~ad. Sci., 467 (1986) 30-39. 248 Kostreva, D.R., Hopp, F.A. and Kampine, ~ ~., Depressor responses to stimulation of sympathetic afferents in monkeys and dogs, Am. J. Physiol., 240 (1981) R23-R28.
249 Kostreva, D.R., Seagard, J.L., Castaner, A. and Kampine, J.P., Reflex effects of renal afferents on the heart and kidney, Am. J. Physiol., 241 (1981) R286-R292. 250 Kow, L.-M., Zemlan, F.P. and Pfaff, D.W., Responses of lumbosacral spinal units to mechanical stimuli rc!ated to analysis of lordosis reflex in female rats, J. Neurophysiol., 43 (1980) 27-45. 251 Kramer, P. and Hollander, W., Comparison of experimental esophageal pain with clinical pain of angina pectoris and esophageal disease, Gastroenterology, 29 (1955) 719743. 252 Kuilmann, R., Cardiovascular reflexes controlling regional sympathetic outflow during coronary artery occlusion, Basic Res. Cardiol., 77 (1982) 507-519. 253 Kumazawa, T., Sensory innervation of reproductive organs. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 115-132. 254 Kuo, D.C. and DeGroat, W.C., Primary afferent projections of the major splanchnic nerve to the spinal cord and gracile m ~leus of the cat, J. Comp. Neurol., 231 (1985) 421-434. 255 Kuo, D.C., Nadelhaft, I., Hisamitsu, T. and DeGroat, W.C., Segmental distribw: and central projections of renal afferent fibers in : cat studied b,, " :~anglionic transport of horseradish peroxidase, J. Comp. Neurol., 216 (1983) 162-174. 256 Kuo, D.C., Oravitz, J.J. and DeGroat, W.C., Tracing of afferent and efferent pathways in the left inferior cardiac nerve of the cat using retrograde and transganglionic transport of horseradish peroxidase, Brain Res., 321 (1984) 111-118. 257 Labate, J.S. and Reynolds, S.R.M., Sensory pathways of the ovarian plexus: an experimental study, Am. J. Obstet. Gynecol., 34 (1937) 1-11. 258 Langley, J.N., The autonomic nervous system, Brain, 26 (1903) 1-26. 259 Lankisch, P.G., Acute and chronic pancreatitis: an update on management, Drugs, 28 (1984) 554-564. 260 Lappe, R.W., Webb, R.L. and Brody, M.J., Selective destruction of renal afferent versus efferent nerves in rats, Am. J. Physiol., 249 (1985) R634-R637. 261 Laskey, W., Schondorf, R. and Polosa, C., Intersegraental connections and interactions of myelinated somatic and visceral afferents with sympathetic preganglionic neurons in the unanesthetized spinal cat, J. Auton. Nerv. $yst., 1 (1979) 69- 76. 262 Lasser, R.B., Bond, J.H. and Levitt, M.D., The role of intestinal gas in functional abdominal pain, New Engl. J. Med., 293 (1975) 524-526. 263 Latimer, P., Campbell, D., Latimer, M., Sarna, S., Daniel, E. and Waterfall, W., Irritable bowel syndrome: a test of the colonic hyperalgesia hypothesis, J. Behav. Med., 2 (1979) 285-295. 264 Laurenberg, S. and Srensen, K.E., Cervical dorsal root ganglion cells with collaterals to both shoulder skin and
227
265
266
267
268 269
270
271 272 273 274
275
276
277 278
279
280
281
the diaphragm. A fluorescent doub|c-tabelling stt~3y i~ the rat. A model for referred pain.'?, Brain Res., 331 (1985) 160-163. Lautt, W.W., Hepatic nerves: a review of their functions and effects, Can. J. Physiol. Pharmacol., 58 (1980) 105123. Layne, J.A. and Bergh, G.S., An experimental study of pain in the human biliary tract induced by spasm of the sphincter of Oddi, Surg. Gynecol. Obstet., 70 (1940) 18-24. Learmonth, J.R., Neurosurgery in the treatment of diseases of the urinary bladder. II. Treatment of vesical pain, J. Urol., 26 (1931) 13-24. Leek, B.F., Abdominal and pelvic visceral receptors, Br. Med, Bull., 33 (1977) 163-168. Lembeck, F. and Skofitsch, G., Visceral pain reflex after pretreatment with capsaicin and morphine, NaunynSchmiedeberg's Arch. Pharmacol., 321 (1982) 116-122. Lew, W.Y.W. and Longhurst, J.C., Substance P, 5-hydroxytryptamine, and bradykinin stimulate abdominal visceral afferents, Am. J. Physiol., 250 (1986) 465-473. Lewis, H.P., Pain in acute and chronic diseases of the liver, Ann. Intern. Med., 35 (1951) 878-888. Lewis, M.I., Reversible ischemic colitis, Dis. Colon Rectum, 16 (1973) 121-126. Lewis, T., Pain, McMillan, London, 1942. Lewis, T. and Kellgren, J.H., Observations related to referred pain, viscerosomatic reflexes and other associated phenomena, Clin. Sci., 4 (1939) 47-71. Lira, R.K.S., Guzman, F., Rodgers, D.W., Gore, K., Braun, C., Dickerson, G.D. and Engle, RJ., Site of action of narcotic and non-narcotic analgesics determined by blocking bradykinin-evoked visceral pain, Arch. Int. Pharmacodyn., 152 (1964) 25-58. Lira, R.K.S., Miller, D.G., Guzman, F., Rodgers, D.W., Rogers, R.W., Wang, S.K., Chao, P.Y. and Shih, T.Y., Pain and analgesia evaluated by the intraperitoneal bradykinin-evoked pain method in man, Ciin. Pharmacol. Ther., 8 (1967) 521-542. Lindgren, I. and Oiivecrona, H., Surgical treatment of angina pectoris, J. Neurosurg., 4 (1947) 19-39. Lipkin, M. and Sleisenger, M.H., Studies of visceral pain: measurements of stimulus intensity and duration associated with the onset of pain in esophagus, ileum and colon, J. Clin. Invest., 37 (1957) 28-34. Littler, W.A., Honour, A.J., Slaight, P. and Stott, F.D., Direct arterial pressure and electrocardiogram in unrestricted patients with angina pectoris, Circulation, 48 (1973) 125-130. Lombardi, F., Bella, P.D., Casati, R. and Malliani, A., Effects of intracoronary administration of bradykinin on the impulse activity of afferent sympathetic unmyelinated fibers with left ventricular endings in the cat, Circ. Res., 48 (1981) 69-75. Longhurst, J.C., Ashton, J.H. and lwamoto, G.A., Cardiovascular reflexes resulting from caps-~cin-stimulated gastric receptors in anesthetized dogs, Circ. Res., 46 (1980) 780-788.
282 Longhurst, J.C. and Dittman, L.E., Hypoxia, bradykinin, and prostaglandins stimulate ischemically sensitive visceral afferents, Am. J. Physiol., 253 (1987) H556-H567. 283 Longhurst, J.C. and Ibarra, J., Sympathoadrenal mechanisms in hemodynamic responses to gastric distension in cats, Am. J. Physiol., 243 (1982) 748-753. 284 Longhurst, J.C., Spilker, H.L. and Ordway, G.A., Cardiovascular re qexes elicited by passive gastric distension in anesthetized cats, Am. J. Physiol., 240 (1981) 539-545. 285 Longhurst, J.C., Stebbins, C.L. and Ordway, G.A., Chemically induced cardiovascular reflexes arising from the stomach of the cat, Am. J. Physiol., 247 (1984) H459H466. 286 MacKenzie, J., Some points bearing on the association of sensory disorders and visceral disease, Brain, 16 (1893) 321-353. 287 MacKenzie, J., Symptoms and their Interpretation, Shaw, London, 1909. 288 MacKenzie-Taylor, D.R., Saatio, K. Heath, G.F. and Rech, R.H., Comparison in rats of mu and kappa opioids on pain of somatic and visceral origin, Physiologist, 28 (1986) 96. 289 Magni, F. and Carobi, C., The afferent and preganglionic parasympathetic innervation of the rat liver, demonstrated by t~e retrograde transport of horseradish peroxidase, J. Auton. Nerv. Syst., 8 (1983) 237-260. 290 Malliani, A., Cardiovascular sympathetic afferent fibers, Rev. Physiol. Biochem. Pharmacol., 94 (1982) 11-70. 291 Malliani, A., The link between transient myocardial ischemia and pain. In: B.S. Singh (Ed.), Silent Myocardial Ischemia and Angina, Pergamon Press, New York, 1988, pp. 34-47. 292 Malliani, A. and Lombardi, F., Consideration of the fundamental mechanisms eliciting cardiac pain, Am. Heart J., 103 (1982) 575-578. 293 Malliani, A., Pagani, '.~.. and Bergamaschi, M., Positive feedback ~ymp~thefic :cflex~ and hypertension, Am. J. Cardiol., 44 (1979) 860-865. 294 Malliani, A., Pagani, M., Pizziaelli, P., Furlan, R. and Guzzetti, S., Cardiovascular reflexes mediated by sympathetic afferent fibers, J. Auton. Nerv. Syst., 7 (1983) 295-301. 295 Malliani, A., Recordati, G. and Schwartz, P.J., Nervous activity of afferent cardiac sympathetic fibres with atrial and ventricular endings, J. Physiol. (Lend.), 229 (1973) 457-469. 296 Malliani, A., Schwartz, P.J. and Zanchetti, A., A sympathetic reflex elicited by experimental coronary artery occlusion, Am. J. Physiol.~ 217 (1969) 703-709. 297 Martin, S.E., Pilkington, D.M. and Longhurst, J.C., Coronary vascular responses to chemical stimuli of abdominal visceral organs, Am. J. Physiol., 256 (1989) H735-H744. 298 Martin, S.J. and Gordham, L.W., Cardiac pain: an experimental study with reference to the tension factor, Arch. Intern. Med., 62 (1938) 840-852.
228 299 McArthur, S.W. and Wakefield, H., Observations on the human electrocardiogram during experimental distension of the gall bladder, J. Lab. Clin. Med., 30 (1945) 349-351. 300 McGowan, J.M., Butsch, W.L. and Waiters, W., Pressure in the common bile duct of man: its relation to pain following cholecystectomy, JAMA, 106 (1936) 2227-2230. 301 McLachlan, E.M., The components of the hypogastric nerve in male and female guinea pigs, J. Auton. Nerv. Syst., 13 (1985) 327-342. 302 McLaughlin, Jr., C.W. and Levering, J.W., The effects of increased intragastric pressure upon thoracic and abdominal a~terial and venous pressures, Surg. Gynecol. Obstet., 58 (1934) 699-704. 303 McLeod, J.G., The representation of the splanchnic afferent pathways in the thalamus of the cat, J. Physiol. (Lond.), 140 (1958) 462-478. 304 McMahon, S.B., Sensory-motor integration in urinary bladder function. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. B~ein i.~es., Vol. 67, Elsevier, Amsterdam, 1986, pp. 245-254. 305 McMahon, S.B., Neuronal arid beh~,viorai consequences of chemical inflammation of rat urinary bladder, Agents Actions, 25 (1988) 231-233. 306 McMahon, S.B. and Abel, C., A model for the study of visceral pain states: chronic inflammation of the chronic decerebrate rat urinary bladder by irritant chemicals, Pain, 28 (1987) 109-127. 307 McMahon, S.B. and Morrison, J.F.B., Two groups of spinal interneurones that respond to stimulation of the abdominal viscera of the cat, J. Physiol. (Lond.), 322 (1982) 21-34. 308 McMahon, S.B. and Morrison, J.F.B., Spinal neurones with long projections activated from the abdominal viscera of the cat, J. Physiol. (Lond.), 322 (1982) 1-20. 309 McNeill, D.L. and Burden, H.W., Convergence of sensory processes from the heart and left ulnar nerve onto a single afferent perikaryon: a neuroanatomical study in the rat employing fluorescent tracers, Anat. Rec., 214 (1986) 441444. 310 McSwiney, B.A. and Suffolk, S.F., Segmental distribution of certain visceral afferent neurones of the pupillo-dilator reflex in the cat, J. Physiol. (Lond.), 93 (1938) 104-116. 3!! Meckler, R.L. and Weaver, L.C., Characteristics of ongoing and reflex discharge of single splenic and renal sympathetic postganglionic fibres in cats, J. Physiol. (Lond.), 396 (1988) 139-153. 312 Mei, N., Sensory structures in the viscera, Prog. Sens. Physiol., 4 (1983) 1-42. 313 Mei, N., Intestinal chemosensmvity, Physiol. Key., 65 (1985) 211-237. 314 Mellanby, J. and Pratt, C.L.G., The reactions of the urinary bladder of the cat under conditions of constant volume, Proc. Roy. Soc. Lond. B, 128 (1940) 186-29i. 315 Mense, S. and Prabhakar, N.R., Spinal termination of nociceptive afferent fibres from deep tissue hi the ca:, Neurosci. Lett., 66 (1986) 169-174.
316 Miller, F.R., Viscero-motor reflexes, II, Am. J. Physiol., 71 (1924) 84-89. 317 Miller, F.R. and Simpson, H.M., Viscero-motor reflexes, Am. J. Physiol., 72 (1925) 231-232. 318 Miller, F.R. and Waud, R.A., Viscero-motor reflexes, IV, Am. J. Physiol., 73 (1925) 329-340. 319 Milne, R.J., Foreman, R.D., Giesler, Jr., G.J. and Willis, W.D., Convergence of cutaneous and pelvic visceral nociceptive inputs onto primate spinothalamic neurons, Pain, 11 (1981) 163-183. 320 Mizumura, K., Tadaki, E. and Kumazawa, T., Respiratory changes induced by activation of testicular afferents in dogs, Pfliigers Arch., 411 (1988) 27-33. 321 Molander, C., Ygge, J. and Dalsgaard, C.-J., Substance P-, somatostatin- and calcitonin gone-related peptide-like immunoreactivity and fluoride resistant acid phosphatase-activity in relation to retrogradely labeled cutaneous, muscular and visceral primary sensory neurons in the rat, New rosci. Lett., 74 (1987) 37-42. 322 Moore, R.M., Some experimental observations relating to visceral pain, Surgery, 3 (1938) 534-555. 323 Moore, R.M. and Singleton, Jr., A.O., A pseudoaffective reflex evoked by injections into the left coronary artery end the peripheral paths of the pain fibers which are cep~cerned, Am. J. Physiol., 113 (1935) 99-100. 324 Morgan, C., Nadelhaft, I. and DeGroat, W.C., The distribution of visceral primary afferents from the pelvic nerve to Lissauer's tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus, J. Comp. Ncuro!., 201 (1981)415-440. 325 Morgan, C., Nadelhaft, I. and DeGroat, W.C., The distribution within the spinal cord of visceral primary afferent axons carried by the lumbar colonic nerve of the cat, Brain Res,, 398 (1Q86) 11-17. 326 Morgan, C., DeGroat, W.C. and Nadeihaft, I., The spinal distribution of sympathetic preganglionic and visceral primary afferent neurons that send axons into the hypogastric nerves of the cat, J. Comp. Neurol., 243 (1986) 23-40. 327 Moriarty, K. and Dawson, A.M., Functional abdominal pain: further evidence that whole gut is affected, Br. Med. J., 284 (1982) 1670-1672. 328 Morley, J., The significance of the afferent impulses from the skin in the mechanism of abdominal pain, Lancet, ii (1929) 1240-1244. 329 Morrison, J.F.B., Splanchnic slowly adapting mechanoreceptors with punctate receptive fields in the mesentery and gastrointestinal tract of the cat, J. Physiol. (Lond.), 233 (1973) 349-361. 330 Morrison, J.F.B., The afferent innervation of the gastrointestinal tract. In: F.P. Brooks and P.W. Evers (Eds.), Nerves and the Gut, Slack, Thorofare, N J, 1977, pp. 297-322. 331 Morrison, J.F.B. and McMahon, S.B., Colonic afferents and their reflexes, Motil. Dig. Tract, 145 (1982) 19-29. 332 Morrison, L.M. and Swalm, W.A., Role of the gastroin-
229 testinal tract in production of cardiac symptoms: experimental and clinical observations, JAMA, 114 (1940) 217223. 333 Mukherjee, S.R., Effect of bladder distension on arterial blood pressure and renal circulation, J. Physiol. (Lond.), 138 (1957) 300-325. 334 Nadelhaft, I. and Booth, A.M., The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: a horseradish peroxidase study, J. Comp. Neurol., 226 (1984) 238-245. 335 Nadelhaft, 1., Roppolo, J., Morgar. C. and DeG~'oat, W.C., Parasympathetic preganglionic aeurons and visceral primary afferents in monkey sacral spinal cord revealed following application of horseradish peroxidase to pelvic nerve, J. Comp. Neurol., 216 (1983) 36-52. 336 Nance, D.M., Burns, J., Klein, C.M. and Burden, H.W., Afferent fibers in the reproductive system and pelvic viscera of female rats: anterograde tracing and immunocytochemical studies, Brain Res. Bull., 21 (1988) 701-709. 337 Nathan, P.W., Sensations associated with micturition, Br. J. Urol., 28 (1956) 126-131. 338 Nathan, P.W. and Smith, M.C., The centripetal pathway from the bladder and urethra within the spinal cord, J. Neurol. Neurosurg. Psychiat., 14 (1951) 262-280. 339 Nerdrum, T., Baker, D.G., Coleridge, H.M. and Coleridge, J.C.G., Interaction of bradykinin and prostaglandin E1 on cardiac pressor reflex and sympathetic afferents, Am. J. Physiol., 250 (1986) R815-R822. 340 Ness, T.J. and Gebhart, G.F., Characterization of neuronal responses to noxious visceral and somatic stimuli in the medial lumbosacral spinal cord of the rat, J. Neurophysiol., 57 (1987) 1867-1892. 341 Ness, T.J. and Gebhart, G.F., Quantitative comparison of inhibition of visceral and cutaneous spinal nociceptive transmission fi-o,,r the midbrain and medulla in the rat, J. Neurophysio]., 58 (1987) 850-865. 342 Ness, T.J. and Gebhart, G.F., Coloreetal distension as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective reflexes in the rat, Brain Res., 450 (1988) 153-169. 343 Ness, T.J. and Gebhart, G.F., Characterization of neurons responsive to noxious coloreetal distension in the TI3-L2 spinal cord of the rat, J. Neurophysiol., 60 (1988) 14191438. 344 Ness, T.J. and Gebhart, G.F., Counterinitation: inhibition of visceral and cutaneous nociception, Neurosci. Abst., 14 (1988) 710. 345 Ness, T.J. and Gebhart, G.F., Characterization of superficial T13-L2 dorsal horn neurons encoding for eolorectal distension in the rat: comparison with neurons in deep laminae, Brain Res., 486 (1989) 301-309. 346 Ness, T.J. and Gebhart, G.F., Differential effects of morphine and clonidine upon visceral and cutaneous nociceptive transmission in the rat, J. Neurophysiol., 62 (1989) 220-230. 346a Ness, T.J. and Gebhart, G.F., Inflammation potentiates
responses to colorectal distension in the rat, Neurosci. Abst., 15 (1989) 847. 347 Neuhuber, W., The central projections of visceral primary aff,~re',t neurons of the inferior mesenteric plexus and hypogastric nerve and the location of the related sensory and preganglionic sympathetic cell bodies in the rat, Anat. Embryol., 164 (1982) 413-425. 348 Neuhuber, W.L. and Niederle, B., Spinal ganglion cells innervating the stomach of the rat as demonstrated by somatopetal transport of horseradish peroxidase, Anat. Embryol., 155 (1979) 355-362. 349 Neuhuber, W.L., Sandoz, P.A. and Fryscak, T., The central projections of primary afferent neurons of greater splanc.hnic and intercostal nerves in the rat, Anat. Embryol., 174 (1986) 123-144. 350 Newman, H.F. and Northrup, J.D., Intraluminal pressure and electrical excitability of the human gall bladder, J. Appl. Physiol., 9 (1956) 121-129. 351 Newman, P.P., Changes in arterial blood pressure following stimulation of the gall bladder, J. Physiol. (Lond.), 119 (1953) 46P-47P. 352 Newman, P.P., Interaction in the visceral sensory areas of the cerebral cortex, J. Physiol. (Loud.), 157 (1961) 29P. 353 Newman, P.P., The representation of some visceral afferents in the anterior lobe of cerebellum, J. Physiol. (Loud.), 182 (1966) 195-208. 354 Newman, P.P. and Paul, D.H., The effects of stimulating cutaneous and splanchnic afferents on cerebellar unit discharges, J. Physiol. (Lond.), 187 (1966) 575-582. 355 Newman, P.P. and Paul, D.H., The projection of splanchnic afferents on the cerebellum of the cat, J. Physiol. (Lond.), 202 (1969) 223-237. 356 Nolan, P.N., Luk, D.E. and Staszewska-Barczak, J., Reflex effects evoked from the parietal pericardium in the dog: comparison with responses from the visceral pericardium, Basic Res. Cardiol., 78 (1983) 654-664. 357 Northover, B.J., The permeability of plasma .nroteins of the peritoneal blood vessels of the mouse, and the effect of substances that alter permeability, J. Patrol. Baeteriol., 85 (1963) 361-370. 358 Ockerblad, N.F. and Carlson, H.E., The distribution of ureterai pain, J. Urol., 39 (1938) 745-750. 359 Ogilvie, W.H., Some notes on the surgical aspects of gall-stone disease, Guy's Hosp. Rep., 75 (1925) 78-97~ 360 Ohman, U., Studies on small intestinal obstruction, Acta Chir. Stand., 141 (1975) 536-549. 361 Oldfield, B.J. and McLachlan, E.M., Localization of sensory neurons traversing the stellate ganglion of the cat, J. Comp. Neurol., 182 (1978) 915-922. 362 Ordway, G.A. and Longhurst, J.C., Cardiovascular reflexes arising from the gallbladder of the cat: effects of capsaicin, bradykinin, and distension, Circ. Res., 52 (1983) 26-35. 363 Ordway, G.A., Boheler, K.R. and Longhurst, J.C., Stimulating intestinal afferents reflexly activates cardiovascular system in cats, Am. J. Physiol., 254 (1988) H354-H360. 364 Ordway, G.A., Longhurst, J.C. and Mitchell, J.H., Stimu-
230
365
366
367
368 369
370
371
372
373 374
375
376
377
378
379
380
lation of pancreatic afferents reflexly activates the cardiovascular system in cats, Am. J. Physiol., 245 (1983) R820-R826. Pagani, N., Pizzinelli, P., Bergamaschi, M. and Malliani, A., A positive feedback sympathetic pressor reflex during the stretch of the thoracic aorta in conscious dogs, Circ. Res., 50 (1982) 125-132. Pagani, M., Pizzinelli, P., Furlan, R., Guzzetti, S., Rimoldi, O., Sandrone, G. and Malliani, A., Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs, Circ. Res., 56 (1985) 175-183. Pahlin, P.E. and Kewenter, J., Reflexogenic contraction of the ileo-cecal sphincter in the cat following small or large intestinal distension, Acta Physiol. Stand., 95 (1975) 126132. Paintal, A.S., Thoracic receptors connected with sensation, Br. Med. Bull., 33 (1977) 169-174. Paintal, A.S., The visceral sensations - some basic mechanisms. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. in Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 3-19. Patei, K.P. and Knuepfer, M.M., Effect of afferent renal nerve stimulation on blood pressure, heart rate and noradrenergic activity in conscious rats, J. Auton. Nerv. Syst., 17 (1986) 121-130. Pavlasek, J., Gokin, A.P. and Duda, P., Visceral pain: responses of the reticular formation neurons to gallbladder distension, J. Physiol. (Paris), 73 (1977) 335-346. Pavlasek, R. and Duda, P., The relation of activity of postsynaptic elements in the spinal cord to propriospinal and spino-bulbo-spinal reflexes, Physiol. Bohemoslov., 20 (1971) 398. Payne, W.W. and Poulton, E.P., Visceral pain in the upper alimentary tract, Quart. J. Med., 17 (1923) 53-80. Payne, W.W. and Poulton, E.P., Experiments on visceral seasation. 1. The relation ot pain to activity in the human esophagus, J. Physiol. (Lond.), 63 (1927) 217-241. Payne, W.W. and Poulton, E.P., Experiments on visceral sensation. II. The 'nausea' and 'sinking': oesophageal reeiexes and counter-irritation, J. Physiol. (Lond.), 65 (1928) 157-172. Pearcy, J.F., Priest, W.S. and Van Allen, C.M., Pain due to temporary occlusion of the coronary arteries in dogs, Am. Heart J., 4 (1929) 390-391. Penfield, W., The neurological mechanisms of angina pec-. toris and i:s relation to surgical therapy, Am. J. Med. Sci., 170 (1925) 864-873. Pert'in, J. et Crousillat, J., Effets de la stimulation des mgcanorgcepteurs splanchniques sur ractivit6 des cellules c6r6belleuses de Purkinje, Exp. Brain Res., 37 (1979) 405416. Perrin, J. and Crousillat, J., Responses of single units in the inferior olive nucleus *.o stimulation of the splanchnic afferents in the cat, J. Auton. Nerv. Syst., 2 (1980) 15-22. Perrin, J. and Crousillat, J., Splanchnic afferent input to the lateral reticular nucleus of the cat, J. Auton. Nerv. Syst., 8 (1983) 383-393.
381 Peterson, D.F. and Brown, A.M., Pressor reflexes produced by stimulation of afferent fibers in the cardiac sympathetic nerves of the cat, Circ. Res., 28 (1971) 605610. 382 Peterson, D.F. and Brown, A.M., Functional afferent innervation of testis, J. Neurophysiol., 36 (1973) 425-433. 383 Pierau, F.K., Fellmer, G. and Taylor, D.C.M., Somatovisceral convergence in cat dorsal root ganglion neurones demonstrated by double-labelling with fluorescent tracers, Brain Res., 321 (1984) 63-70. 384 Polland, W.S. and Bloomfield, A.L., Experimental referred pain from the gastrointestinal tract. I. The esophagus, J. Clin. Invest., 10 (1931) 435-452. 385 Pomeranz, B., Wall, P.D. and Weber, W.V., Cord cells responding to fine myelinated afferents from viscera, muscle and skin, J. Physiol. (Lond.), 199 (1968) 511-532. 386 Poole, J.W., Sammartano, R.J. and Boley, S.J., Hemodynamic basis of the pain of chronic mesenteric ischemia, Ann. Intern. Med., 153 (19~7) 171-180. 387 Pozo, F., Fueyo, A., Esteban, M.M. and Rojo-Ortega, J.M., Blood pressure changes after gastric mechanical and electrical stimulation in rats, Am. J. Physiol., 249 (1985) 739-744. 388 Prabhakar, N.R., Marek, W. and Loeschke, H.H., Altered breathing pattern elicited by stimulation of abdominal visceral afferems, J. Appl. Physiol., 58 (1985) 1755-1760. 389 Price, D.D., Bushnell, M.C. and ladarola, M.J., Primary afferent and sacral dorsal horn neuron responses to vaginal probing in the cat, Neurosci. Lett., 26 (1981) 67-72. 390 Ravidin, I.S., Royster, H.P. and ~/anders, G.B., Reflexes originating in the common duct giving rise to pain simulating angina pcctoris, Ann. Surg., 115 (1942) 1055-1065. 391 Ray, B.S. and Neill, C.L., Abdominal visceral sensation in man, Ann. Surg., 126 (1947) 709-724. 392 Reading, A.E., The internal structure of the McGill Patt~ Questionnaire in dysmenorrhea patients, Pain, 7 (1979) 353-358. 393 Reeve, E.B., Nanson, E.M. and Rundle, F.F., Observations on inhibitory respiratory reflexes during abdominal surgery, Clin. Sci., 10 (1951) 65-87. 394 Reimann, K.A. and Weaver, L.C., Contrasting reflexes evoked by chemical activation of cardiac afferent nerves, Am. J. Physiol., 239 (1980) H316-H325. 395 Richter, J.E., Barish, C.F. and Castell, D.O., Abnormal sensory perception in patients with esophageal chest pain, Gastroenterology, 91 (1986) 845-852. 396 Risholm, L., Studies on renal colic and its treatment by posterior splanchnic block, Acta Chir. Scand. Suppl., 184 (1954) 1-64. 397 Ritchie, J., Pain from distension of the pelvic colon by infating a balloon in the irritable colon syndrome, Gut, 14 (1973) 125-132. 398 Ritchie, J., Pain in IBS, Pract. Gastroenterol., 3 (1979) 16-23. 399 Ritchie, J., Mechanisms of pain in the irritable bowel syndrome. In: N. Read (Ed.), Irritable Bowel Syndrome, Grune and Stratton, New York, 1985, pp. 163-171. 400 Re~ato, E.F., Chu, W.H., MuUen, J.L. and Rosato, F.E.,
231
401
402
403 404
405 406
407
408
409
410
411
412
413
414
415
416 417
418
Peritoneal lavage treatment of experimental pancreatitis, J. Surg. Res., 12 (1972) 138-140. Rose, J.D., Response properties and anatomical organization of pontine and medullary units responsive to vaginal stimulation in the cat, Brain Res., 97 (1975) 79-93. Rose, J.D., Responses of midbrain neurons to genital and somatosensory stimulation in estrous and anestrous cats, Exp. Neurol., 49 (1975) 639-652. Ross, J., On the segmental distribution of sensory disorders, Brain, 10 (1888) 333-361. Roughgarden, J.W., Circulatory changes associated with spontaneous angina pectoris, Am. J. Med., 41 (1966) 9.~7961. Routledge, J.H. and Elliot, H., Pain studies in pelvic viscera, Am. J. Obstet. Gynecol., 83 (1962) 701-709. Rubia, F.J., The projection of visceral afferents to the cerebellar cortex of the cat, Pfliigers Arch., 320 (1970) 97-110. Rubia, F.J. and Phelps, J.B., Responses of the cerebellar cortex to cutaneous and visceral afferents, Pfliigers Arch., 314 (1970) 68-95. Ruch, T.C., Pathophysiology of pain. In: T.C. Ruch, J.D. Patton, J.W. Woodbury and A.L. Lowe (Eds.), Neurophysiology, Saunders, Philadelphia, PA, 1961, pp. 350-368. Rucker, H.K. and HoUoway, J.A., Viscerosomatic convergence onto spinothalamic tract neurons in the cat, Brain Res., 243 (1982) 155-157. Ruge, D. and Wetzel, N., The surgical relief of intractable abdominal pain, Surg. Clin. N. Am., 34 (1954) 269-275. Riihle, W., Dembowsky, K., Czachurski, J. and Seller, H., Segmental distribution of afferent fibers in the left inferior cardiac nerve of the cat studied by anterograde transport of horseradish peroxidase, Neurosci. Lett., 56 (1985) 353358. Ryall, R.W. and Piercey, M.F., Visceral afferent and efferent fibers in sacral ventral roots in cats, Brain Res., 23 (1970) 57-65. Rybicki, D.J., Longhurst, I.C. and Kaufman, M.P., Stimulation of splanchnic afferents reflexly relaxes tracheal smooth muscle in dogs, Am. J. Physiol., 55 (1983) 427-432. Sarnoff, S.J. and Yamada, S.I., Evidence from reflex control of arterial pressure from abdominal receptors with special reference to the pancreas, Circ. Res., 7 (1959) 325-335. Satpathy, N.K. and AI-Sattar, N.A., The effects of acute oesophageal distension on arterial blood pressure, E.C.G. and respiration in the dog, Indian J. Physiol. Pharmacol., 28 (1984) 105-114. Sawchenko, P.E. and Friedman, M.I., Sensory functions of the liver - a review, Am. J. Physiol., 236 (1979) RS-R20. Schmauss, C., Shimohigashi, Y., Jensen, T.S., Rodbard, D. and Yaksh, T.L., Studies on spinal opiate receptor pharmacology. III. Analgetic effects of enkephalin dimers as measured by cutaneous-thermal and visceral-chemical evoked responses, Brain Res., 337 (1985) 239-215. Schondorf, R. and Polosa, C.~ Effects of urinary bladder afferents on respiration, J. Appl. Physiol., 48 (1980) 826832.
419 Scho:,dorf, R., Laskey, W. and Polosa, C., Upper thoracic sympathetic neuron responses to input from urinary afferents, Am. J. Physiol., 245 (1983) R311-R320. 420 Schi'ager, V.L. and Ivy, A.C., Symptoms produced by distension of the gallbladder and biliary tracts: a clinical and experimental study, Surg., Gynecol. Obstet., 47 (1928) 1-13. 421 ¢" ' ,.,c~zer, M. and Spencer, W.A., Convergence of visceral and cutaneous afferent pathways in the lumbar spinal cord, Brain Res., 14 (1969) 331-348. 422 Selzer, M. and Spencer, W.A., Interactions between visceral and cutaneous afferents in the spinal cord: reciprocal primary afferent fiber depolarization, Brain Res., 14 (1969) 349-366. 47~t Se.~sle, B.J., t ]u, J.W., Amano, N. and Zhong, ~.~.,Convergence of cut~.neous, tooth pulp, visceral, neck and muscle afferents onto nociceptive and non-nociceptive neurones in trigeminal subnucleus c,~udalis (medullary dorsal horn) and its implications for referred pain, Pain, 27 (1986) 219-235. 424 Sharkey, K.A., Sobrino, J.A. and Cervero, F., Evidence for a visceral afferent origin of substance P-like immunoreactivity in lamina V of the rat thoracic spinal cord, Neuroscience, 22 (1987) 1077-1083. 425 Sherrington, C.S., The Integrative Action of the Nervous System, Yale Univ. Press, New Haven, CT, 1906. 426 Shukla, M., Dey, P.K. and Tripathi, S.N., Effect of graded distension of urinary bladder on arterial blood pressure and neurohumors in rabbits, Indian J. Physiol. Pharmacol., 29 (1985) 159-164. 427 Sicuteri, F., FanciuUacci, M. and Anselmi, B., Bradykinin release and inactivation in man, Int. Arch. Allergy, 22 (1963) 77-84. 428 Silen, W., Cope's Early Diagnosis of the Acute Abdomen, 16th edn., Oxford Univ. Press, New York, 1983. 429 Simon, O.R. and Schramm, L.P., The spinal course and medullary termination of myelinated renal afferents in the rat, Brain Res., 290 (1984) 239-247. 430 Sinclair, D.C., Weddeli, G. and Feindel, W.H., Referred pain and associated phenomena, Brain, 71 (1948) 184-211. 431 Skoglund, R.W., McRoberts, J.W. and Ragde, H., Torsion of the s,pe:.rmatic cord: a review of the literature and an analysis of 70 new cases, J. Urol., 104 (1970) 604-607. 432 Smits, J.F.M. and Brody, M.J., Activation of afferent renal nerves by intrarenal l,radykinin in conscious rats, Am. J. Physiol., 247 (1984) 1003-1008. 433 Sonoda, H., Ikenoue, K. and Yokota, T., Periaqueductal gray inhibition of viscerointercostal and galvanic skin reflexes, Brain Res., 369 (1986) 91-102. 434 Staniland, J.R., Ditchburn, J. and DeDombal, F.T., Clinical presentation of acute abdomen: study of 600 patients, Br. Med. J., 3 (1972) 393-398. 435 Staszewska-Barczak, J. and Dusting, G.J., Sympathetic cardiovascular reflex initiated by bradykinin-induced stimulation of cardiac pain receptors in the dog, Clin. Exp. Pharmacol. Physiol., 4 (1977) 443-452. 436 Staszewska-Barczak, J., Ferreira, S.H. and Vane, J.R., An excitatory nociceptive cardiac reflex elicited by bradykinin
232 and potentiated by prostaglandins and myocardial ischemia, Circ. Res., 10 (1976) 314-327. 437 Staszewska-Wooley, J., Luk, D.E. and Nolan, P.N., Cardiovascular reflexes mediated by capsaicin sensitive cardiac afferent neurones in dogs, Cardiovasc. Res., 20 (1986) 897-906. 438 Stebbins, C.L., Smith, R.C. and Longhurst, J.C., Effect of prostaglandins on bradykinin-induced visceral-cardiac reflexes, Am. J. Physiol., 249 (1985) H155-H163. 439 Stein, J.H. (Ed.), Internal Medicine, 2rid edn., Little, Brown and Co., Boston, MA, 1987. 440 Stein, R.D., Genovesi, S., Demarest, K.T. and Weaver, L.C., Caps~cin ',re~.',ment attenuates the reflex excitation of sympathetic activity caused by chemical stimulation of intestina~ afferent nerves, Brain Res., 397 (1986) 145-151. 441 Stein, R.D. and Weaver, L.C., Multi- and single-fibre mesenteric and renal sympathetic responses to chemical stimulation of intestinal receptors in cats, J. Physiol. (Lond.), 396 (1988) 155-172. 442 Strassman, P., Mason, P., Moskowitz, M. _and Maciewicz, R., Response of brainstem trigeminal neurons to electrical stimulation of the dura, Brain Res., 379 (1986) 242-250. 443 Stulrajter, V., Pavlasek, J., Strauss, P., Duda, P. and Gokin, A.P., Some neuronal autonomic and behavioral correlates to visceral pain elicited by gall-bladder stimulation, Activ. Nerv. Sup. (Praha), 20 (1978) 203-209. 444 Sturge, W.A., The phenomena of angina pectons and their bearia~ ~v-'bii ,,~;~h~:x,~y v,'~'¢,,u~tcr-irritation,Brain, 5 (1883) 492-510. 4~4a Sugiura, Y., Terui, N. and Hosoya, Y., Differences in distribution of central terminals between visceral and somatic unmyelinated (C) primary afferent fibers, J. Neurophysiol., 62 (1989) 834-840. 445 Sutton, D.C. and Lueth, H.C., Pain: experimental production of pain on excitation of the heart and great vessels, Arch. Intern. Med., 45 (1930) 827-867. 446 Swarbrick, E.T., Bat, L., Hegarty, J.E. and Williams, C.B., Site of pain from the irritable bowel, Lancet, i-ii (1980) 443-446. 446a Sylv6n, C., Angina pectoris. Clinical characteristics, neurophysiological and molecular mechanisms, Pain, 36 (1989) 145-168. 447 Taber, R.I., Greenhouse, D.D., Rendell, J.K. and Irwin, S., Agonist and antagonist interactions of opioids on acetic acid-induced abdominal stretching in mice, J. Pharmacol. E:~p. Ther., 169 (1969) 29-38. 448 Tagushi, H., Masuda, T. and Yokota, T., Cardiac sympathetic afferent input onto neurons in nucleus ventralis posterolateralis in cat thalamus, Brain Res., 436 (1987) 240-252. 449 Takahashi, M. and Yokota, T., Convergence of cardiac and cutaneous afferents onto neurons in the dorsal horn of the spinal cord in the cat, Neurosci. Lett., 38 (1983) 251-256. 450 Tattersall, J.E.H., Cervero, F. and Lumb, B.M., Effects of reversible spinalization on the visceral input to viscero-
somatic neurons in the lower thoracic spinal cord of the cat, J. Neurophysiol., 56 (!986) 785-796. 451 Tattersall, J.E.H., Cervero, F. and Lumb, B.M., Viscerosomatic neurons in the lower thoracic spinal cord of the cat: excitations and inhibitions evoked by splanchnic and somatic nerve volleys and by stimulation of brain stem nuclei, J. Neurophysiol., 56 (i986) 1411-1423. 452 Taylor, D.E.M., Reflex effects of slow bladder filling on the blood pressure in cats, Quart. J. Exp. Physiol., 50 (1965) 263-270. 453 Taylor, D.E.M., Afferent pathways and efferent mechanisms in the bladder viscero-vascular reflex, Quart. J. Exp. Physiol., 53 (1968) 262-272. 454 Taylor, D.E.M., Some observations on the effect of slow distension of the bladder and the rectum on cardiac output in the cat, J. Physiol. (Lond.), (1973) 100-101. 455 Theobald, G.W., Referred pain, in particular that associated with dysmenorrhea and labour: a preliminary report, Br. Med. J., 2 (1936) 1307-1308. 456 Thies, R. and Foreman, R.D, Inhibition and excitation of thoracic spinoreticular neurons by electrical stimulation of vagal afferent nerves, Exp. Neurol., 82 (1983) 1-16. 457 Thornburn, W., The sensory distribution of spinal nerve, Brain, 16 (1893) 355-374. 458 Tobey, J.C. and Weaver, L.C., Pressoreceptor modulation of renal but not splenic s)~rnpathetic reflexes, Am. J. Physiol., 252 (1987) R26-R33. 459 Tyner, C.F., Splanchnic nerve activation of single cells in the cat's postcruciate motosensory cortex, Exp. Neurol., 63 (1979) 76-93. 460 Uchida, Y. and Murao, S., Excitation of afferent cardiac sympathetic nerve fibers during coronary occlusion, Am. J. Physiol., 226 (1974) 1094-1099. 461 Uchida, Y. and Murao, S., Bradykinin-induced excitation of ~fferent cardiac sympathetic nerve fibers. Jpn. Heart J., 15 (1974) 84-91. 462 Ueda, H., Uchida, Y. and Kamisaka, K., Mechanism of the reflex depressor effect by kidney in dog, Jpn. Heart J., 8 (1967) 597--606. 463 Ueda, H., Uchida, Y. and Kamisaka, K., Distribution and responses of the cardiac sympathetic receptors to mechanically induced circulatory changes, Jpn. Heart J., 10 (1969) 70-81. 464 Vance, W.H. and Bowker, R.C., Spinal origins of cardiac afferenls from the region of the left anterior descending artery, Brain Res., 258 (1983) 96-100. 464a Vecchiet, L., Giamberardino, M.A., Dragani, L. and Albe-Fessard, D., Pain from renal/ureteral calcinosis: evaluation of sensory thresholds in the lumbar area, Pain, 36 (1989) 289-295. 465 Villanueva, L., Cadden, S.W. and LeBars, D., Diffuse noxious inhibitory controls (DNIC): evidence for postsynaptic inhibition of trigeminal nucleus caudalis convergent neurones, Brain Res., 321 (1984) 165-168. 466 Vogt, A., Vetterlein, F., Ri, H.D. and Schmidt, G., Excitation of afferent fibers in the cardiac sympathetic nerves
233 induced by coronary artery occlusion and injection of bradykinin. The influences of acetylsalicylic acid and dipyron, Arch. Int. Pharmacodyn., 239 (1979) 86-98. 467 Von Euler, C. and Sj~strand, T., The elicitafion of viscero-motor reflexes, Acta Physiol Y~:and., 14 (194"/) 363-372. 468 Waldrop, T.G., lwamoto G.A. and Ordway, G.A., Cardiovascular reflexes arising from the gallbladder and pancreas in spinal and decerebrate cats, Brain Res., 299 (1984) 358-362. 469 Waldrop, T.G., Rybicki, K.J., Kaufman, M.P. and Oralway, G.A., Activation of visceral thin-fiber afferents increases respiratory output in cats, Resp. Physiol., 58 (1984) 187-196. 470 Watkins, A.L., Reflex responses of the nictitating membrane and the blood pressure to distension of the bladder and rectum, Am. J. Physiol., 121 (1939) 32-39. 471 Weaver, L.C., Cardiac sympathetic afferent influences on renal nerve activity, J. Auton. Ncrv. Syst., 3 (1981) 253263. 472 Weaver, L.C°, Organization of sympathetic responses '.o distension of urinary bladder, Am. J. Physiol., 248 (1984) 236-240. 473 Weaver, L.C., Danos, L.M., Oehl, R.S. and Meckler, R.L., Contrasting reflex influences of cardiac afferent nerve during coronary occlusion, Am. J. Physiol., 240 (1981) H620-H629. 474 Weaver, L.C., Genovesi, S., Stella, A. and Zanchetti, A., Neural, hemodynamic, and renal responses to stimulation of intestinal receptors, Am. J. Physiol., 253 (1987) H1167Hl176. 475 Weaver, L.C., Macklem, L.J., Reimann, K.A., Meckler, R.L. and Oehl, R.S., Organization of thoracic sympathetic afferent influences on renal nerve activity, Am. J. Physiol., 237 (1979) H44-H50. 476 Weber, R.N., Blair, R.W. and Foreman, R.D., Effects of intracardiac injections of bradykinin on thoracic spinal neurons in the cat, Exp. Neurol., 78 (1982) 703-715. 477 Weiss, S. and Davis, D,, The significance of the afferent impulses from the skin in the mechanism of visceral pain: skin infiltration as a useful therapeutic measure, Am. J. Med. Sci., 176 (1928) 517-536. 478 Wennmalm, A., Chanh, P.H. and Junstad, M., Hypoxia causes prostaglandin release from perfused rabbit hearts, Acta Physiol. Stand., 91 (1974) 133-135. 479 Wernoe, T.B., Viscero-cutane Reflexe, Pfliigers Arch., 210 (1925) 1-34. .480 White, J.C., Sensory innervation of the viscera, Res. Publ. Ass. Nerv. Ment. Hlth, 23 (1943) 373-390. 481 White, J.C. and Bland, E.F., The surgical relief of severe angina pectoris, Medicine, 27 (1948) 1-42. 482 White, J.C., Garry, W.E. and Atkins, J.A., Cardiac innervation: experimental and clinical studies, Arch. Surg., 26 (1933) 765-786. 483 White, J.C. and Sweet, W.H., Pain and the Neurosurgeon: a 40 Year Experience, Thomas, Springfield, IL, 1963, pp. 525-589.
484 White, J.C., Verlot, M.G. and Ehrentheil, O., Neurogenic disturbances of the colon and their investigation by the colonmetrogram, Ann. Surg., 112 (1940) 1042-1057. 485 xtnaa;,.,,,~p,~ -~,.-,--,.-~-, J.G., Sensory innei-vation of the lungs and airways. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Voi. 67, Elsevier, Amsterdam, 1986, pp. 49-64. 486 Wid6n, L., Cerebellar representation of high threshold affercnts in the splanchnic nerves with observations on the cerebellar projection of high threshold somatic afferent fihre~ Acta Physiol. Scand., 117. Suppl. 33 (1955) 1-69. 487 Willis, W.D., The Pain System, Karger, Basel, 1985. 488 Willis, W.D., Visceral inputs to sensor pathways in the spinal cord. In: F. Cervero and J.F.B. Morrison (Eds.), Visceral Sensation. Prog. Brain Res., Vol. 67, Elsevier, Amsterdam, 1986, pp. 207-225. 489 Winning, A.J. and Widdicombe, J.G., The effect of lung reflexes on the pattern of breathing in cats, Resp. Physiol., 27 (1976) 253-266. 490 Woodworth, R.S. and Sherrington, C.S., A pseudaffective reflex and its spinal path, J. Physiol. (Lond.)~ 31 (1904) 234-243. 491 Woolf, C.J. and Wall, P.D., Relative effectiveness of Cprimary afferent fibers of different origins in evolOng a prolonged facilitation of the flexor reflex in the rat, J. Neurosci., 6 (1986) 1433-1442. 492 Woolf, H.G., Hardy, J.D. and Goodell, H., Studies on pain. Measurement of the effect of morphine, codeine and other opiates on the pain threshold and an analysis of their relation to the pain experience, J. Clin. Invest., 19 (1940) 659-680. 493 Woollard, H.H. and Carmichael, E.A., The testis and referred pain, Brain, 56 (1933) 293-303. 494 Woollard, H.H., Roberts, J.E.H. and Carmichael, E.A., An enquiry into referred pain, Lancet, i (1932) 337-338. 495 Wurster, R.D. and Randall, W.C., Cardiovascular responses to bladder distension in patients with spinal transection, Am. J. Physiol., 228 (1975) 1288-1292. 496 Wyngaarden, J.B. and Smith, Jr., L.H. (Eds.), Cecil's Textbook of Medicine, 18th edn., Saunders, Philadelphia, PA, 1988. 497 Wyss, J.M. and Donovan, M.K., A direct projection from the kidney to the brain~tem, Brain Res., 298 (1984) 130134. 498 Yamamoto, S., Araki, K. and Kikuch/, M., Abdominal muscle reflexes of pelvic nerve origin in cats, Exp. Neurol., 4 (1961) 345-357. 499 Yokota, T., Masuda, T., Tagushi, H. and Koyama, N., Viscerosomatic convergence onto nociceptive neurons in the shell region of nucleus ventralis posterolateralis. In: R.F. Schmidt, H.-G. Schaible and C. Valhe-Hinz (Eds.), Fine Afferent Nerve Fibers and Pain, VCH Verlagsgesellschaft, Weinheim, 1987, pp. 427-437. 500 Yokota, T., Nozuma, N°; Nishikawa, Y., Koyama, N., Tagushi, H., Masuda, T., Nomura, T. and Asato, F., Thalamic mechanisms of nociception: nociceptive neurons in VPL of cat thalamus. In: H. Tagushi, Y. Oomura and "
234 M. Ito (Eds,), Biowarning System in the Brain, Univ. Tokyo Press, Tokyo, 1988, pp. 17-30. 50_' Zolliag¢.,', R., Oi,~,~:rvations following distension of the gallbladder and common duct in man, Proc. Soc. Exp. Biol. Meal. (NY), 30 (1933) 1260-1264.
502 Zollinger, R., Significance of pain and vomiting in chole. lithiasis, JAMA, 105 (1935) 1647-1652. 503 Zollinger, R. and Walter, C.W., Localization of pain following faradic stimulation of the common bile duct, Proc. Soc. Exp. Biol. Med. (NY), 35 (1936) 267-273.
