77

Bruin Research Reviews, 17 (1992) 77-99 0 1992 Elsevier Science Publishers B.V. All rights reserved 0165-0173/92/$05.00

BRESR 90144

Full-length

reviews

Vagal afferent modulation of nociception A. Randich a and G.F. Gebhart b aSchool of Social and Behavioral Sciences, Department of Psychology, The University of Alabama at Birmingham, Birmingham, AL 35294-1170 (USA) and b Department of Pharmacology, University of Iowa, Iowa City, IA (USA) (Accepted 21 April 1992)

Key words: Vagal afferent; Nociception; Pain; Analgesia

CONTENTS 1. Introduction

........................................................................................

78

2. Peripheral stimuli that modulate nociception and whose effects depend on the integrity of cervical, thoracic or cardiac vaeal afferents . 2.1. Morphine ............................. ........................... . 2.1.1. Behavioral measures of nociception ...... ........................... 2.1.2. Spinal nociceptive transmission ......... ........................... . 2.2. o-Ala’-methionine enkephalinamide .......... ........................... 2.2.1. Behavioral measures of nociception ...... . ........................... 2.2.2. Spinal nociceptive transmission ......... ........................... .. 2.3. Veratrine ............................. ........................... 2.3.1. Behavioral measures of nociception ...... ... ........................... 2.4. Serotonin ............................. . ........................... 2.4.1. Behavioral measures of nociception ...... ... ........................... 2.5. S-nitrosocysteine ........................ ... ........................... 2.5.1. Behavioral measures of nociception ...... ... ........................... 2.6. Volume expansion ....................... ... ........................... 2.6.1. Behavioral measures of nociception ...... . ........................... 2.7. Electrical stimulation ..................... ........................... 2.7.1. Behavioral measures of nociception ...... .. ........................... 2.7.2. Spinal nociceptive transmission ......... .. ...........................

78 79 79 80 80 80 81 81 81 82 82 83 83 83 83 83 83 84

3. Peripheral stimuli that modulate nociception via activation of either diaphragmatic vagal or subdiaphragmatic

86 87 87 87 87 88

vagal afferents

3.1. Morphine.. ..................................................................................... 3.1.1. Behavioral measures of nociception ................................................................ 3.2. Electrical stimulation. .............................................................................. 3.2.1. Behavioral measures of nociception ................................................................ 3.2.2. Spinal nociceptive transmission ................................................................... 4. Central nervous system relays for cervical vagal and subdiaphragmatic vagal effects on nociception ........................... 4.1. Nucleus tractus solitarius ............................................................................ .............................................................................. 4.2. Nucleusraphemagnus 4.3. focus coeruleus/subcoeruleus ........................................................................ 4.4. Rostra1 ventrolateral medulla ......................................................................... 4.5. Caudal ventrolateral medulla ......................................................................... 4.6. Periaqueductal grey ................................................................................ 4.7. Ventrolateral pontine tegmentum ...................................................................... 4.8. Mid-collicular decerebration .........................................................................

Correspondence to: A. Randich, School of Social and Behavioral Sciences, Department

.......

88 88 89 92 92 92 92 93 93

of Psychology, The University of Alabama at Birmingham, 201 Campbell Hall, 1300 University Boulevard, UAB Station, Birmingham, AL 35294-1170, USA. Fax: (1) (205) 975-6110.

78 s. Spinal

cord .................... 5.1. Spinal blocks ............... 5.2. Ventrolateral funiculi ......... 5.3. Dorsolateral funiculi ..........

6. Spinal neurotransmitters 7. Is vagal activation 8. Future

Ui

of vagal effects

aversive or noxious?

94

areas of investigation

95

9. Summary

96

Acknowledgements References

97

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .._._.._..........................................

.._.....___......,..,....,,.,..,.,,.,,...,._.__._.....___.._,....,..,,,,,...,,..,..........

1. INTRODUCTION

For many years, vagal afferents arising from thoracic and abdominal viscera have been recognized for their role in the control of the circulation, respiration and gastrointestinal function. The study of vagal afferents in the modulation of nociception, however, is a relatively recent event. The first systematic investigations on vagal afferent modulation of nociception occurred approximately 10 years ago in a series of reports by Foreman and colleagues 5*h*93,94. They showed that activation of either cervical or thoracic vagal afferents generally inhibited resting, somatic-evoked or bradykinin-evoked activity of thoracic spinothalamic tract neurons believed to be important in the perception of cardiac pain. Subsequently, Randich and Maixner64 provided a review of pharmacological, physiological and anatomical data, suggesting that peripheral and central systems regulating cardiovascular function closely paralleled those identified as important for the control of nociception. They proposed that increases in vagal afferent activity should diminish nociceptive reflexes. Since these initial publications, numerous studies have confirmed the role of vagal afferents in nociception and also delineated some of the neuroanatomical network underlying vagal-nociceptive interactions. Not surprisingly, the brainstem nuclei identified as relays for vagal afferent modulation of nociception correspond to those nuclei independently identified as important for the modulation of nociception. Moreover, the study of vagal afferent modulation of nociception has also afforded new insights into mechanisms of pain and analgesia. For example, it is now clear that the antinociceptive effects of lesser doses of morphine given intravenously (i.v.) involve activation of It is unlikely that this outcome vagal afferents”,‘l. would have been predicted by previous theories of CNS and spinal substrates mediating the effects of

97

systemic morphine administration’9~‘08, but directly follows from the view of interactions between cardiovascular and pain modulatory systems64. A large number of studies investigating vagal modulation of nociception have been reported in recent years and it is appropriate to review these data. This review attempts to assimilate and integrate these data. It also suggests new directions for research in this area by critically evaluating studies of vagal modulation of nociception in terms of both the peripheral stimulus treatment and the response measure of nociception. This is followed by a review of CNS relays, spinal pathways and spinal neurotransmitters identified as important for vagal effects on nociception. 2. PERIPHERAL CEPTION INTEGRITY DIAC

STIMULI

AND

VAGAL

WHOSE

OF

THAT EFFECTS

CERVICAL,

MODULATE DEPEND

THORACIC

NOCION OR

THE CAR-

AFFERENTS

In the following sections, we summarize treatments that produce alterations in nociception and depend on the integrity of cervical, thoracic or cardiac vagal afferents. These treatments include chemical, physiological and electrical stimulation. This section deals only with evidence concerning peripheral mechanisms of action. The sections on CNS relays, spinal pathways and spinal neurotransmitters for these treatments are summarized later. It is also important to note several issues that bear on the studies summarized in this section. First, in studies of chemical and physiological stimulation, there is no evidence that the treatment directly activates vagal afferents to modulate nociception. It is possible that some of these treatments result in the release of a peripheral mediator that, in turn, affects vagal function. On the other hand, many of the chemical treatment studies have shown that the outcomes were a consequence of a specific interaction with the appro-

79 priate peripheral receptor complex and that the ultimate effect of either chemical or physiological treatments depend on the integrity of vagal afferents. The issue of whether the effects of any of the chemical treatments in the following sections are due to direct activation of vagal afferents will not be easy to demonstrate. Single-unit recording of vagal afferent fibers can be used to provide converging evidence that vagal afferents are activated by the treatment in question, but this type of evidence does not address the issue of whether the treatment directly activates vagal afferents or whether the observed change in vagal afferent activity is related to the observed changes in nociception. Second, electrical stimulation is used in many of these studies because it provides a convenient and reproducible means of studying vagal influences on n~iception. In studies of electrical stimulation, there is usually non-selective activation of all vagal afferents, although to some extent this depends on either the parameters or the location of stimulation used in a particular study, or concomitant manipulation of other variables (e.g., neonatal capsaicin treatment to selectively destroy C-fibers). We assume that many of the chemical and physiological treatments described in this section selectively activate at least a subset of the vagal

TAIL

afferents identified through the use of electrical stimulation as impo~ant to the modulation of nociception. Finally, cardiopulmonary vagal, diaphragmatic vagal (DVAG) and subdiaphragmatic vagal (SDVAG) afferents all have been demonstrated to affect nociception in at least some species. These effects have been dissociated in some studies by either selective stimulation of vagal branches or neuronal degeneration. However, in most studies of electrical stimulation of cardiopulmonary vagal afferents, it is not possible to specify the origin of the stimulated afferents. This review will not provide a detailed discussion of either sensory inne~ation by the vagus or CNS projections of the vagus, since extensive reviews on these subjects are available elsewhere15~‘6~25~37-39~56*58~~. 2.1. Morphine 2.1.1. ~ehauiorul ~~~~r~ of ~cicept~~ Intravenous (i.v.1 administration of morphine results in dose-dependent (0.1-2.5 mg/kg) inhibition of the nociceptive tail flick (TF) reflex in the pentobarbital-anesthetized rat”,‘l. The antinociception occurs within 1.0 s of i.v. morphine administration and persists during a 20 min assessment period. Inhibition of the TF reflex obtained with lesser doses of i.v. morphine (OS-l.0 mg/kg) are significantly attenuated by bilateral cervical vagotomy

FLICK

B-

6-

4. 0.5 mg/kg 21 -5

B

10 r

6. *w 0

CERvlcKVAGOT~ 2.5 mq/kg

TIME (MN)

TIME (MIN)

Fig. 1. The effect of various doses of i.v. morphine (0.1, 0.5, 1.0 and 2.5 mg/kgI on the TF reflex evoked by noxious heat in sham-operated and bilateral cervical vagotomized rats. TF trials were administered 0.16, l-, 2-, 3-, 4-, S-, lo-, 1% and 20-min after iv. morphine administration. B, baseline TF latency and 10 s is the cut-off latency. Bilateral cetvical vagotomy significantly attenuated the antinociception at all doses, with the greatest attenuation occurring at lesser doses and earlier test trials. From Randich et al.“‘.

80

throughout a 20 min assessment period, although the greatest attenuation occurs during the initial 3-5 min following morphine administration. There is an antinociceptive effect of lesser doses of i.v. morphine that is manifested after 3-5 min and is relatively unaffected by bilateral cervical vagotomy, although the effect of bilateral cervical vagotomy on i.v. morphineproduced antinociception can be demonstrated over the entire 20 min testing period (see section 5). Inhibition of the TF reflex obtained with a greater dose of morphine (2.5 mg/kg) is attenuated by bilateral cervical vagotomy only during the period immediately following i.v. morphine administration (0.16-l min). Presumably, there is a direct CNS and/or spinal effect with the greater dose of i.v. morphine that masks the ability to detect the vagal influence with longer delays to testing. Fig. 1 shows the effects of various doses of i.v. morphine on the TF reflex evoked by noxious heat in intact and bilateral vagotomized rats. It is unlikely that bilateral cervical vagotomy attenuates i.v. morphine-produced antinociception by simply eliminating a tonic vagal modulatory influence on some direct CNS and/or spinal cord effect of morphine. Prior administration of the peripheral-acting opioid receptor antagonist naloxone methobromide results in an attenuation of i.v. morphine-produced antinociception to the same extent as bilateral cervical vagotomy, regardless of whether lesser or greater doses of i.v. morphine are used’“. While there is no direct evidence that i.v. morphine activates vagal opioid receptors to produce antinociception, it is the most plausible explanation of these effects. Opiate receptors in the nodose ganglion undergo fast axonal transport towards the periph8,1”9,110 and a recent studyiu’ indicates that IL-, Sery and K-receptors comprise approximately 75%, 3% and 22% of vagal opioid receptors, respectively. Preliminary studies from our laboratory indicate that i.v. morphine-produced inhibition of the TF reflex is likely due to an effect on low affinity p2 - rather than either S or K-opioid receptors. Specifically, antinociception is produced by i.v. administration of the selective k-opioid agonist DAMPGO, but not by either the selective S-opioid agonist DPDPE or the K-opioid agonist U50488H. Further, the antinociceptive effects of both DAMPGO and i.v. morphine are abolished by prior administration of the selective p.,-opioid receptor antagonist B-FNA, but not by the selective pi-opioid receptor antagonist naloxonazine. 2.1.2. Spinal nociceptive transmission i.v. administration of lesser doses of morphine (0.5 or 1.0 mg/kg) results in inhibition of responses of wide-dynamic range (class 2) lumbosacral spinal dorsal horn neurons to noxious

1.0 MG/KG

MORPHINE

-5~....,.......,,....,........,, .16

3

6

9

12

15

16

21

TIME (MN)

Fig. 2. Summary data for the effects of i.v. administration of 1.0 mg/kg of i.v. morphine on responses of lumbosacral spinal dorsal horn neurons to noxious heating of the hindpaw (52°C) in intact (N = 5 units) and bilateral cervical vagotomized rats (N = 5 units). i.v. morphine produced immediate inhibition of unit responses to heat in intact rats. Bilateral cervical vagotomy significantly attenuates this inhibition during the 21-min assessment period, although a weak spinal effect of morphine is apparent 3-6 min after drug administration in these rats. From Randich et al.“.

heating of the glabrous skin of the hindpaw”. Similar to the data obtained with the TF reflex, inhibition of spinal nociceptive transmission begins within 10 s of drug administration, persists during a 20 min assessment period and is significantly attenuated in rats with bilateral cervical vagotomy. Fig. 2 shows summary data for the effects of i.v. morphine administration on spinal nociceptive transmission in intact and bilateral vagotomized rats. 2.2. o-Ala 2-methionine enkephalinamide 2.2.1. Behavioral measures of nociception

o-Ala2methionine enkephalinamide (DALA) is a synthetic methionine-enkephalin analog that does not readily enter the CNS on i.v. administrations9 and was used in initial studies of vagal influences on nociception for this reason. i.v. administration of DALA results in dose-dependent (5-500 pg/kg) inhibition of the TF reflex in both lightly anesthetized and conscious rats3,29,62-66.The antinociception produced by DALA is eliminated by bilateral cervical vagotomy6’, but is unaffected by total subdiaphragmatic vagotomy29. DALA-induced antinociception is also antagonized by iv. administration of the opioid receptor antagonist naloxone6’, but this effect is presumably due to its peripheral action, since intrathecal administration of naloxone at the level of the lumbar enlargement does not affect the antinociception produced by i.v. DALA3. Willette and Sapru lo7 demonstrated that the cardiorespiratory effects of DALA may involve stimulation of pulmonary J-receptors, with no apparent effect on either pulmonary stretch or pulmonary irritant receptors. Thus, vagal pulmonary J-receptors may be potential sites of action for mediating the antinociceptive effects of DALA. As noted in the previous discus-

81 sion of morphine, preliminary studies in our laboratory on the cardiovascular and antinociceptive effects produced by i.v. administration of selective CL-, S- and K-opioid receptor agonists would suggest that the antinociceptive effects of DALA, like morphine, are due to activation of p2-opioid receptors. However, the cardiovascular responses produced by i.v. DALA indicate that it has both I_L-and S-opioid effects. Thus, it may be premature to assume that the cardiorespiratory data implicating DALA activation of J-receptors are necessarily relevant to the effects of DALA on antinociception (i.e., J-receptor activation could reflect a a-receptor rather than p-receptor phenomenon and relate only to cardiorespiratory function). In any case, the non-selective nature of DALA may preclude its further usefulness to understanding vagal influences on nociception. 2.2.2. Spinal nociceptive transmission There are no published data on the effects of i.v. administration of DALA on spinal nociceptive transmission. However, data collected by Ness and Randich (unpublished observations) indicate that i.v. administration of DALA generally exerts either an initial facilitatory followed by an inhibitory effect or only an inhibitory effect on responses of lumbosacral spinal dorsal horn neurons to noxious heating of the hindpaw in the rat. Fig. 3 shows

an example of i.v. DALA-induced inhibition of responses of a lumbosacral spinal dorsal horn neuron to noxious heating of the hindpaw and accompanying changes in arterial blood pressure. It is unclear whether further systematic studies of DAL,A on spinal nociceptive transmission should be pursued given its non-selective characteristics. The currently available selective CL-,6- and K-opioid receptor agonists DAMPGO, DPDPE and U-50488H, respectively would be more appropriate for further investigations of opioid activation of vagal afferents and modulation of nociception. 2.3. Vera trine 2.3.1. Behavioral measures of nociception Veratrine

is a combination of veratrum alkaloids that non-specifically activates peripheral receptors. It was originally studied because it has potent stimulatatory effects on vagal afferents. i.v. administration of veratrine results in dose-dependent (5-100 pg/kg) inhibition of the TF reflex to noxious heat in either conscious or lightly anesthetized rats66969.The antinociception produced by i.v. veratrine is eliminated by bilateral cervical vagotomy, but is unaffected by subdiaphragmatic vagotomy 29. Thus, despite the fact that veratrine is non-selective, the results obtained with bilateral cervi-

pre -DALA

totalno.~

u

‘,“in

I I

50°C

impubs i

t

-5

heat

-2

1

4

7

la

1s

$5

15

u

Time (ml)

Fig. 3. Example of the effects of i.v. DALA on spinal cutaneous nociceptive transmission. Peristimulus-time histograms (1 s bin width) and corresponding oscillographic records of a lumbar spinal unit’s response to 50°C heating of the hindpaw are illustrated at the left before (pre-DAL41 and at two times after i.v. administration of DAL& the period of heating is shown below. To the right, the changes in mean ABP (above) and the unit’s responses (total number of impulses) to 50°C heating of the hindpaw are plotted against time on the abscissa. The administration of DALA is indicated. From Ness, Randich and Gebhart (unpublished data).

82 cal vagotomy indicate that the antinociception is specific to activation of receptors in the thoracic region and depends on the integrity of vagal afferents. i.v. administration of naloxone failed to affect this antinociception@. iv. administration of veratrine also results in dosedependent (5-100 pg/kg) inhibition of the paw-lick response in the hot-plate assay69. However, no other studies have used this measure of nociception for determining other characteristics of i.v. veratrine-modulation of nociception. 2.4. Serotonin 2.4.1. Behavioral measures of nociception In a series of

studies by Meller and colleagues46-50, i.v. administration of serotonin (5-HT) produced dose-dependent (6192 pg/kg; ED,, = 44 kg/kg) inhibition of the TF reflex in pentobarbital-anesthetized and conscious rats. The antinociception produced by i.v. 5-HT at the effective dose 50 (ED,,) is abolished following either bilateral cervical vagotomy or nodose ganglionectomy, but is unaffected by subdiaphragmatic vagotomy46. Interestingly, the antinociception produced by i.v. 5-HT is enhanced following either bilateral stellate or petrosal ganglionectomy. Similarly, in studies of spontaneously hypertensive rats (SHRs), Wistar-Kyoto normotensive rats (WKYs) and Sprague-Dawley normotensive rats, transection of the aortic depressor nerve resulted in a significant increase in sensitivity to i.v. 5-HT-induced

inhibition of the TF reflex”. These data suggest that aortic depressor and other peripheral fibers may provide strong tonic inhibitory influences on the vagally mediated inhibitory effects of 5-HT. The antinociceptive effect of 5-HT requires dual activation of 5-HT, and 5-HT, receptors. i.v. administration of either a-methyl 5-HT (a 5-HT, receptorselective agonist) or 2-methyl 5-HT (a 5-HT, receptorselective agonist) were without influence on the TF reflex, whereas a 1:l combination of these two agonists produced the same profile of dose-dependent antinociception as 5-HT 49. The outcomes of dual 5-HT, and 5-HT, activation are shown in Fig. 4. Converging evidence for the dual role of 5-HT, and 5-HT, receptors in mediating antinociception produced by i.v. 5-HT is provided by the finding that the antinociception is significantly attenuated by i.v. administration of either xylamidine (5-HT, receptor antagonist) or ICS 205-930 (5-HT, receptor antagonist) as shown in Fig. 4. i.v. 5-HT-produced antinociception is also eliminated in rats treated as neonates with capsaicin5’, a C-fiber neurotoxin. These data suggest that vagal Cfiber afferents mediate the effects antinociceptive effects of i.v. 5-HT. Interestingly, the capsaicin treatment did not affect vagally mediated cardiovascular responses produced by iv. 5-HT, suggesting that vagal afferents mediating the antinociceptive effects of 5-HT (C-fibers) differ from those mediating the cardiovascular effects. Similar outcomes have been observed in

Antagonists

Agonists 0 7 i

0 0

a-me

5-HT 5-HT

w 2-me

S-HT

+ 2-me

5-HT , J

5-HT xylam xylam

+ ICS

6-

6-

0

0 0 0

5-HT

a-me

I B

1

I

3

10

30

doso h/kg)

I

I

100

300

0

b

I

I

8

6

3

10

30

I 100

4 300

dose bdkd

Fig. 4. Effects of 5-HT receptor agonists on the TF reflex (left) and of 5-HT antagonists on 5-HT-produced inhibition of the TF reflex (right). In both panels, i.v. 5-HT (0) is shown to produce a dose-dependent inhibition of the TF reflex. In the left panel, neither the 5-HT, receptor agonist a-methyl-S-HT (a-me-5-HT) nor the 5-HT, receptor agonist 2-methyl-5-HT (2-me-5-HT) affected TF latency over the dose range studted. However, a 1:l combination of these two receptor-selective agonists produced a dose-dependent inhibition of the TF reflex, replicating the effects of 5-HT. In the right panel, the antinociceptive effects of i.v. 5-I-IT are shown to be attenuated by iv. pretreatment with either the 5-HT, receptor antagonist xylamidine (xylam, 50 pg/kg) or the 5-I-P, receptor antagonist ICS 205-930 (ICS, 100 +g/kg); pretreatment with the combination abolished the antinociceptive effects of 5-HT. From Meller et al. 49 and Meller et al. (unpublished data).

83 studies employing electrical stimulation to activate vagal afferents (see subsection 2.7). 2.5. S-Nitrosocysteine 2.5.1. Behavioral measures of nociception i.v. adminis-

tration of S-nitrosocysteine, a putative endothelium-derived relaxing factor (EDRF), produces dose-dependent inhibition (0.5-10 pmol; ED,, = 4.4 pmol) of the nociceptive TF reflex in pentobarbital-anesthetized rat$‘. This effect was blocked by bilateral cervical vagotomy, but no other information is available on this interesting manipulation. 2.6. Volume expansion 2.6.1. Behavioral measures of nociception i.v. adminis-

tration of the volume expander Ficoll inhibits the TF reflex in conscious rats43. The magnitude of inhibition is significantly correlated with central venous pressure and the inhibitory effect is attenuated following unilateral resection of the right cervical vagus. Unilateral vagal resections are used in studies of conscious rats, since they either do not survive bilateral cervical vagotomy .or show marked respiratory debilitation. i.v. administration of Ficoll also results in inhibition of the TF reflex in SHR@‘. SHRs manifest antinociception at significantly lesser volumes of Ficoll than does a SHR X Wistar Kyoto (WKY) rat F, backcross with borderline hypertension. In turn, both SHRs and the F, backcross manifest antinociception at significantly lesser volumes of Ficoll than normotensive WKYs. The differences in the amount of Ficoll required to produce antinociception in SHRs, the F, backcross and WKYs may reflect differential excitability of vagal afferents resulting from cardiopulmona~ receptor resetting in these rats55,81-84*97*g8, but this has not been directly evaluated. 2.7. Electrical stimulation Electrical stimulation of vagal afferents has been extensively used in studies of vagal modulation of nociception. The limitations of this technique were noted earlier, but it is worth restating that DVAG and SDVAG afferents are also all activated when an electrode is placed on either the cervical or thoracic vagus. However, some studies have demonstrated the independence of these branches in their capacity to produce changes in nociception. It should also be noted that appropriate control studies have shown that the outcomes obtained with electrical stimulation of either the cervical or thoracic vagus are a consequence of stimulation of vagal afferents rather than vagal efferents.

2,%1. Behavioral measures of nociception Electrical stimulation of either the right or left cervical vagus (CVAG) can either facilitate or inhibit the TF reflex in rats61@,67*74,78. Facilitation of the TF reflex is produced by electrical stimulation of CVAG afferents at lesser intensities (typically between 2.5 and 20 PA, 20 Hz, 2 ms> and the magnitude of facilitation does not depend on the baseline latency of the TF reflex within a range of 2.6-6.3 s78. Facilitation has not been shown to be intensi~-dependent within the range of intensities assessed to date”. That is, greater facilitation does not occur at the least magnitude of vagal stimulation (e.g., 2.5 PA). The facilitatory effect is also unaffected by neonatal capsaicin treatment”, indicating that vagal C-fibers are unlikely to mediate the facilitatory effect. This is supported by evaluations of intensity- and latency-dependent effects of CVAG stimulation on responses of spinal dorsal horn neurons to noxious stimuli (see below). Inhibition of the TF reflex is usually obtained with electrical stimulation intensities greater than 30 PA and the magnitude of the inhibition is intensity-dependent74. Analyses of the inhibitory effects of CVAG stimulation indicate that the inhibitory function abruptly increases at intensities of stimulation of approximately 80% of the intensity required for complete inhibition of the TF reflex. One explanation for this abrupt transition is that the facilitatory effect ‘interferes’ with the determination of the pure inhibitory effect of CVAG afferent stimulation, resulting in what appears to be a quanta1 change in the inhibitory function. By this we mean that the vagal afferents producing the inhibitory effect have a higher threshold for activation than those required for the facilitatory effect. Recent studies showed that CVAG stimulation at an intensity of 1000 PA is incapable of inhibiting the TF reflex in 50% of a group of rats treated as neonates with capsaicin; in the remaining 50% of the group, CVAG stimulation intensities of at least 2000 PA were required to inhibit the TF reflex, intensities several fold greater than those required in untreated control or vehicle-treated rats”. These results support the view that vagal C fiber afferents are important for the inhibitory effect produced by CVAG stimulation, CVAG afferent inhibition of the TF reflex is also dependent on the frequency and pulse width of stimulation, with 20 Hz and 2 ms pulses providing the optimal stimulus parameters (i.e., least intensity) for producing complete inhibition of the TE reflex”. The antinociception is virtually instantaneous in onset and typically outlasts the duration of vagal stimulation by 5-10 s at the threshold used to inhibit the TF reflex to a cut-off latency. Stimulating at current intensities ex-

84

ceeding the threshold for inhibition to an arbitrary cut-off latency of 7 s rest&s in antinociception lasting up to 1 min following termination of stimulation. Maixner et a1.41*42reported that the jaw opening reflex (JOR) evoked by noxious tooth pulp stimulation in ar-chloralose anesthetized cats is inhibited by electrical stimulation of the cervical, thoracic or cardiac branches of the vagus. Electrical stimulation of cervical, cardiac or thoracic vagal branches in a conditioning-test (CT) paradigm resulted in inhibition of the JOR at CT intervals greater than 50 ms with maximal inhibition occurring at a CT interval of 200 ms. There were no significant differences in the efficacy of stimulation of different branches of the vagus to produce inhibition of the JOR (Le., cardiac = thoracic = cervical). Similar outcomes of vagal modulation of the JOR in a CT manipulation were reported by Chase et al.1”s14in immobilized encephale isole cats. Similar to the effects of CVAG stimulation on the TF reflex, facilitation of the JOR occurred at all CVAG stimulation intensities tested at CT intervals of smaller than 10 ms. 2.7.2. Spinal twcicegrive t~ansrn~si~~ ‘I’heis and Foreman93 performed extracellular recordings of 51 thoracic (Ti-T3) spinal neurons in the cat; 43% of the sample could be antidromically activated by electrical stimulation in either the ipsilateral or contralateral spinomedullary junction. Many of these units also responded to both electrical stimulation of the sympathetic chains or pinching of the skin. Electrical stimulation of the cervical vagus (trains of either 50-82 Hz, 10 ps and 5-33 V or lo-120 Hz, 100-500 ps and 4-15 Vf inhibited the resting activity of 51% of the units, increased activity of 12% of the units, both inhibited and facilitated 4% of the units and had no effect in 33% of the units. Thus, the resting activity of the majority of units were inhibited by CVAG stimulation. Ammons et a1.5 subsequently studied the responses of 71 thoracic spinothalamic tract neurons located in laminae I, IV, V and VII in the monkey (Macaca fascicular~). These included class-2 (convergent), class3 (nociceptive specific) or class-3 neurons with inhibito~ input from hair. Each of the neurons could be excited by manipulations in its somatic receptive field and also by electrical stimulation of cardiac sympathetic afferents. Left thoracic vagal stimulation resulted in inhibition of the resting activity of 61% of the units, excitation of 13% of the units, excitation followed by inhibition of 4% of the units and no effect on 22% of the units. The degree of inhibition of resting activity produced by vagal stimulation was linearly related to the magnitude of cell activity prior to stimulation and this relationship did not vary as a function of

cell type. Vagal stimulation also inhibited responses of 100% of neurons (!Q = 32) to somatic stimuli, primarily naxious pinch but also including non-noxious stimuli, such as hair movement. In a second study, Ammons et al.h used a CT paradigm to examine the effects of electrical stimulation of the cervical vagus on the temporal course of visceral-evoked responses of the same spinothalamic tract neurons characterized in the preceding section. The noxious visceral stimulus was either electrical stimulation of cardiac sympathetic afferents or ~ntra-atria1 injections of bradykinin (2 ,u;g/kg). Neurons whose resting activity was inhibited by vagal stimulation were evaluated in the CT paradigm, assessing the time course of vagal influences during electrical stimulation of sympathetic afferents. In 79% of the cells, stimulation of the cervical vagus 50 ms prior to sympathetic nerve stimulation produced maximal inhibition of responses to both A&and C-fiber input. The response to sympathetic afferent stimulation at A~-intensity tended to recover at longer CT intervals, whereas substantial inhibition of sympathetic afferent C-fiber input could be maintained with CT intervals up to 200 ms. In a similar manner, electrical stimulation of the thoracic vagus inhibited intra-atria1 bradykinin-evoked activation of 100% of thoracic neurons tested. Administration of bradykinin alone resulted in a mean increase in cell discharge from 9.1 to 29.2 impulses/s. Vagal stimulation reduced the bradykinin-induced increase to 11.7 impulses/s and the cells recovered their original response to bradykinin after cessation of vagal stimulation. Cervical vagotomy proximal to the stimulating electrode blocked these effects. More recently, Chandler et a1.12 studied 42 cervical (C,-C,) and 34 thoracic (T,-T,) spinothalamic tract neurons in monkeys and found no differences in the inhibitory effects of vagal stimulation on either resting or evoked activity of these cells as a function of whether the cells (1) were affected by stimulation of cardiopulmonary sympathetic afferents (60% were excited in the cervical regions) or (21 had proximal or distal cutaneous receptive fields. There were also no differences between the effects of vagal stimulation on the resting activity of either cervical or thoracic units: inhibition was observed in 40% of cervical and 44% of thoracic units, an increase was observed in 5% of cervical and 3% of thoracic units and no effect was observed in 55% of cervical and 53% of thoracic units. They concluded that electrical stimulation of vagal afferents results in a general inhibitory effect at these levels of the spinal cord that transmit nociceptive information. While this pattern of effects may well be the case, none

85 of these studies systematically varied stimulation parameters. Thus, it is not clear whether the same percentage of effects would have been obtained with a parametric evaluation of stimulation parameters. Hobbs et al.27 in studies of 40 spinothalamic tract neurons located in segments T,-S, of the monkey (M~caca ~~~c~c~~~~~~) showed that electrical stimulation of the right cervical vagus reduced resting activity of 48% of the units, excited 5% of the units and did not affect 48% of the units. Stimulation of the left cervical vagus reduced resting activity of 42% of the units, excited 8% of the units and did not affect 50% of the units. Stimulation of either the right or left vagus had the same effect on 85% of these units. In six units selected on the basis of being inhibited during electrical stimulation of CVAG afferents, responses evoked by either urinary bladder distension to 80 cmH,O or noxious pinch of the hindlimb were also inhibited by CVAG stimulation. In the lumbosacral spinal cord in the rat, electrical stimulation of the cervical vagus has both facilitatory and inhibitory effects on both the resting and noxious heat-evoked responses of spinal dorsal horn neurons. The following summarizes data from a series of studies75-77,79.In all these studies, primarily class-2 neurons were examined from all laminae of the lumbar spinal dorsal horn of the rat. These units responded to nonnoxious brush, noxious pinch and noxious heat applied to the glabrous skin of the plantar surface of the ipsilateral hind foot. Most of these neurons were not tested for antidromic invasion from areas rostra1 to the lumbosacral region; however, in a separate study directly comparing the effects of WAG stimulation on identified versus non-identified class-2 spinothalamic tract neurons in the rat79 there were no quantitative or qualitative differences in the effects of CVAG stimulation on these types of units. In these studies of 200 units, noxious heat-evoked responses of 38% of the units were only inh~ited by electrical stimulation of CVAG afferents and were referred to as INHIB units. The inhibitory effect of CVAG stimulation depends on the intensity, frequency and pulse width of CVAG stimulation. Parameters of 20 Hz, 2 ms and intensities ranging between 130 and 180 @A were required for inhibition of responses to 50% of control values and are comparable to those parameters required for inhibition of the TF reflex described previously. Cumulative sum anaIyses75 (CUSUM) were used to determine the latency to the onset of the inhibition following the onset of CVAG stimulation. These analyses indicated that the latency from the onset of vagal stimulation to inhibition of lumbosacral units is approximately 91 ms. CVAG stim-

ulation also decreased the slope, but did not affect the threshold of stimulus-respond unctions (SRFs) at temperatures ranging from 42 to 52°C. Heat-evoked responses of 50% of the unit sample were facilitated by lesser intensities of CVAG stimulation, but were progressively inhibited as the intensity of CVAG stimulation was increased. These units were referred to as BIPHASIC units. BIPHASIC units typically had facilitatory thresholds near 30 PA and an inhibitory threshold near 90 PA. BIPHASIC units also show frequency and pulse-width dependency. Thus, an inhibitory effect is observed at some intensity of CVAG stimulation in 88% of all units studied, when INHIB and BIPHASIC units are considered together. Heat-evoked responses of 9% of the unit sample’ showed only facilitation during CVAG stimulation at

t

2 i!

0

J, , , , , ,

% cants iz 150 1 z s s

P

E 0

0

50

100

200

% control E 150 E 0 r c 100

300

INHIB

1, 0

(

50

100

200

t

1

300

---#._A

&

2 %,

!-

0 0

100

200

300

400

5001000

VAS fntensity &A) Fig. 5. Summarydata illustrating the effects of electrical stimulation of CVAG afferents on lumbar spinal unit responses to noxious heating (50°C) of the hindpaw. In all panels, responses to noxious heat are plotted as% of control against the intensity of CVAG stimulation. In the top panel, CVAG stimulation is shown to facilitate unit responses at lesser and to inhibit responses of the same units at greater intensities of stimulation (i.e., the effects are BIPHASIC). In the middle panel, only inhibitory (INIIIB) effects are produced by stimulation and in the bottom panel only facilitatory (FACIL) effects are produced by stimulation. Data are from”,“.

86

intensities up to 800 PA and were referred to as FACIL units. The intensity at which CVAG stimulation began to affect FACIL units was less than 50 PA, but there was no clear intensity-dependent modulation of FACIL units, similar to data reported in studies of the TF reflex74. The apparent latency for facilitation of responses of lumbosacral units to noxious heat was determined by a CUSUM method75 and is approximately 278 ms. Thus, significantly greater time is required for the facilitatory effect of CVAG stimulation to occur than for the inhibitory effect noted previously (i.e., 91 ms). SRFs for FACIL units show a decrease in threshold, but no change in the slope compared to control SRFs. Finally, heat-evoked responses of 3% of the unit sample were unaffected by CVAG stimulation. Fig. 5 presents summary data from these experiments involving CVAG afferent modulation of FACIL, INHIB and BIPHASIC units described above. In all the preceding examples, CVAG stimulation was studied with respect to responses of lumbosacral units evoked by noxious heating of the foot. An analysis of changes in resting activity of these same units during CVAG stimulation indicates that about 40% are decreased from a mean of 2.55 to 0.92 impulses/s, about 35% are increased from a mean of 2.55 to 6.31 impulses/s and about 25% are unaffected. The effect of CVAG afferent stimulation on resting activity of these units, however, does not predict what effect the same intensity of CVAG stimulation will have on responses of the same unit to noxious heating of the skin. Therefore, these data on effects of CVAG stimulation on the resting activity of lumbosacral units responding to noxious thermal stimulation differ substan-

10 Hz -

10s

1

no.

400 -

control

.-: ; .r -u 2 10 yA VAS

t

In the following sections, we summarize treatments that produce alterations in nociception by activation of

total

$-li13-

.II L,,,I ,111 1

3. PERIPHERAL STIMULI THAT MODULATE NOCICEPTION VIA ACTIVATION OF EITHER DIAPHRAGMATIC OR SUBDIAPHRAGMATIC VAGAL AFFERENTS

impulses

AL

&

tially from those data reported on the effects of thoracic vagal stimulation on resting activity of cervical and thoracic spinothalamic units studied by Ammons and colleagues 5,h. There may also be other differences between lumbosacral and thoracic neurons. Lumbosacral units that are only inhibited by CVAG stimulation (INHIB units) comprise about 38% of the sample in the Ren et. al studies in the rat, but comprise 61% of the thoracic sample in the Ammons et al. studies in the monkey. Similarly, BIPHASIC units comprise approximately 50% of the sample in rat studies, but only 4% of the sample in monkey studies. As noted previously, it is unclear whether these are real or apparent differences, since stimulation parameters were systematically varied only in the rat studies. Finally, vagal stimulation appears to affect a greater total percentage of lumbosacral neurons responding to noxious heat than thoracic or cervical neurons responding to noxious ‘visceral’ stimulation (i.e., cardiac nerve stimulation or intraatrial administration of bradykinin). This may reflect the modality of nociceptive input, although unpublished work from our laboratory indicates that CVAG stimulation does modulate the responses of units in the medial lumbosacral spinal cord to the noxious colorectal distention in a manner similar to noxious heat (see Fig. 6).

~O/.LAVAS

: $I n t

0

300 0

200 -

0

0

looO-

, 0

1, 25

stimulation

0

,

50 75 intensity (PA)

, 0 100

I Fig. 6. Example of the biphasic effects of CVAG afferent stimulation on spinal visceral nociceptive transmission. Peristimulus-time histograms (1 s bin width) and corresponding oscillographic records of a sacral spinal unit’s response to noxious colorectal distension (80 mmHg) are illustrated at the left in the absence (above) and during two intensities of VAS; the period of colorectal distension is shown below. At the right, changes in the unit’s response to distension (total number of impulses) are potted against the intensity of stimulation on the abscissa. From Zhou, Randich and Gebhart (unpublished data).

87 diaphragmatic vagal afferents (DVAG) and subdiaphragmatic vagal afferents (SDVAG) afferents. As noted above, the integrity of SDVAG afferents are not necessary for the antinociception produced by i.v. administration of DAL& veratrine or 5-HT. Nonetheless, SDVAG afferents are important for a small, but significant, component to the antinociception produced by i.v. morphine. Electrical stimulation of SDVAG afferents produces behavioral antinociception and inhibition of spinal nociceptive transmission in the rat. The outcomes of studies using these latter stimuli are summarized below.

100

r

?

T/

60 -

!i 6 +u L

60 . 40 -

_,k

20 O- .---. -201-‘-‘.‘.‘.‘.’ 0 10

/-.

--q

--*

/e

/-. 20

30

40

PERCENT

50

I.‘.‘., 70 60

60

THRESHOLD

3.1. Morphine 3.1.1.

3.2. Electrical stimulation 3.2.1. Behavioral measures

of nociception

Electrical stimulation of either the dorsal or ventral branch of the subdiaphragmatic vagus produces inhibition of the TF reflex in pentobarbital-anesthetized rats2,74,99*‘0’.SDVAG-produced antinociception depends on the intensity, frequency and pulse width of electrical stimulation99. The current intensities required for inhibition are generally greater than those required for inhibition produced by CVAG stimulation. However, unlike CVAG stimulation, facilitation of the TF reflex is not produced by SDVAG stimulation, Fig. 7 presents intensity, frequency and pulse-duration functions for SDVAG modulation of the TF reflex. The intensity function obtained with SDVAG stimulation reveals a graded increase in inhibition of the TF reflex, unlike the abrupt increase that is observed with stimulation of the cervical vagus. Thus, it seems likely that the facilitatory effect observed with low intensities of CVAG stimulation derives primarily from the cardiopulmonary region, an outcome consistent with the effects of CVAG stimulation on the jaw opening reflex at short CT intervals described previously. Selective nerve transection studies showed that antinociception produced by stimulation of the dorsal

100

*

Behavioral measures of nociception

There is a small, but statistically significant contribution of SDVAG afferents to antinociception produced by a lesser dose (0.5 mg/kg) of i.v. morphine”. The subdiaphragmatic effect occurs approximately 4 min after i.v. administration and persists for a 20 min observation period. Similarly, Steinman, Faris and Olney9’ reported a small antinociceptive effect of intraperitoneal administration of morphine (10 mg/kg) that was significantly attenuated following subdiaphragmatic vagotomy. At the present time, however, there is no other information on the role of SDVAG afferents in contributing to morphine antinociception.

90

CURRENT

0 1900

P 9 B F

700 500 300 100

10

20

30

FREQUENCY

r.

.

40

50

(Hz)

‘i\ 0 0.1



0.5

? 2.0

1.0 PULSE

WIDTH

(msj

Fig. 7. Intensity, frequency and pulse-width functions for SDVAG modulation of the nociceptive TF reflex. The intensity function for SDVAG stimulation (20 Hz, 2 ms) is graded with only inhibition of the TF reflex. Percent MPE, percent maximal possible effect where 0%, no change in TF latency from baseline and lOO%, inhibition of the TF reflex to a 10 s cut-off latency. Percent threshold inhibition denotes each current intensity tested as a percentage of that required to inhibit the TF reflex to the cut-off latency of 10 s. Frequency (2 ms pulse width) and pulse-width (20 Hz) functions are presented as the minimum intensity of SDVAG stimulation necessary to inhibit the TF reflex to the 10 s cut-off latency. Data are from Thurston and Randich99.

subdiaphragmatic vagus depends on the right cervical vagus and antinociception produced by stimulation of the ventral subdiaphragmatic vagus depends on the left cervical vagus*. There is little, if any, crossing of SDVAG afferents with respect to the production of antinociception. Most importantly, the antinociceptive effects of CVAG afferent stimulation are independent of those produced by stimulation of SDVAG afferents. Aicher et aL2 injected the toxin ricin into the dorsal subdiaphragmatic vagus. This resulted in a significant reduction in the number of SDVAG fibers (as confirmed morphologically by cell loss in the nodose ganglia) and elimination of the capacity of dorsal SDVAG afferents to support antinociception. However, this treatment did not affect the capacity of right CVAG afferents to produce antinociception.

Maixner et al.4’,42 reported that DVAG stimulation results in significant inhibition of the JOR produced by electrical stimulation of the tooth-pulp in (Ychloralose-anesthetized cats. The inhibition of the JOR produced by DVAG stimulation was relatively weak when compared to that produced by cervical, thoracic or cardiac vagal stimulation. 3.2.2. Spinal nociceptiue transmission Ammons et a1.5, in the context of studying vagal influences on thoracic projection neurons in monkeys, reported that electrical stimulation of the vagus below the level of the heart failed to affect responses of ten thoracic neurons that were evaluated. In a study described previously, Hobbs, Oh, Chan‘O] 601 50 1 i

CONTROL

60

50 40

30 20 10 0

40

100 pA SDVAG I

dler and Foreman2’ also examined the effects of stimulating abdominal diaphragmatic vagal afferents on resting activity of 35 lumbosacral spinothalamic tract neurons. This resulted in inhibition of resting activity of only 11% of the units, increased activity of 3% of the units and had no effect on 86% of the units. In contrast, electrical stimulation of CVAG afferents resulted in inhibition of resting activity of 48% of the units, increased activity of 6% of the units and no effect on 45% of the units. Thus, the Oklahoma group has consistently failed to find significant effects of electrical stimulation of abdominal vagal afferents on resting activity of primate lumbosacral spinothalamic tract neurons. However, one must interpret these negative outcomes with some caution. The effect of abdominal vagal stimulation was assessed with respect to changes in resting activity of lumbosacral neurons. In studies of Ren and colleagues described previously”, no consistent relationship was found between the effects of CVAG stimulation on resting activity of lumbosacral units relative to its effects on noxious heat-evoked responses of lumbosacral neurons in the rat, yet CVAG stimulation inhibited noxious-evoked responses of 88% of these units. In preliminary studies in the rat from our laboratory, electrical stimulation of the dorsal SDVAG produces intensity-dependent inhibition of approximately 68% of class-2 and 89% of class-3 units to noxious heating of the hindpaw, but affected the resting activity (greater than 10% change from baseline) of only 4% of class-2 units and 12% of class-3 units. Fig. 8 pre: :nts an example of one unit inhibited by graded intensities of SDVAG stimulation. 4. CENTRAL

NERVOUS SYSTEM RELAYS FOR CER-

VICAL VAGAL

AND SUBDIAPHRAGMATIC

VAGAL

EFFECTS ON NOCICEPTION 70. 60. 50. 40

4.1. Nucleus tractus solitarius 200 IJA SWAG

30,

52”

C

HEAl

Fig. 8. An example of the effects of SDVAG stimulation on responses of a lumbosacral spinal dorsal horn neuron to noxious heat. Peristimulus-time histograms (1 s bin width) of a unit’s response to 15 s of noxious heating (52°C) of the hindpaw before (control) and during SDVAG stimulation at various intensities of stimulation (2 ms, 20 Hz). This unit is progressively inhibited by increasing intensities of SDVAG stimulation. Data from Thurston and Randich (unpublished data).

Virtually all vagal afferents from the cardiopulmonary regions terminate bilaterally in the caudal third of the nucleus tractus solitarius39q56. Many putative neurotransmitters are contained in vagal afferents and include glutamate, substance P and 5-HT26,73,96.Any of these, as well as other substances localized there, are potential candidates for mediating the effects of vagal afferents at second-order neurons in the NTS. Currently, there is evidence that both glutamate and substance P serve as neurotransmitters of primary afferents mediating antinociception derived from activation of CVAG afferents. Bilateral microinjection of the non-selective glutamate receptor antagonist r-d-

89 g~ut~y~gly~ine into the NT!3 attenuates inhibition of the TF reflex produced by electrical stimulation of the cervical vagus 61. This outcome is consistent with the demonstration that glutamate is released in the NTS during electrical stimulation of the cervical vagus73. In addition, neonatal capsaicin treatment significantly increases the current intensity required for CVAG stimulation to produce inhibition of the TF reflex, suggesting that substance P may also serve as a primary transmitter for CVAG afferents ‘O. Similarly, Meller et aLso have shown that neonatal capsaicin treatment produces a significant rightward shift of the dose-response curve for i.v. 5-HT-produced antinociception. There is both direct and indirect evidence that the NTS is the initial relay for vagal afferent inhibition of the TF reflex and lumbosacral spinal nociceptive transmission. In these and other studies of CNS relays to follow, either reversible local anesthesia or irreversible cell destruction has been achieved by localized microinjection into brainstem nuclei of either lidocaine or the somata-selective neuroto~n ibotenic acid88, respectively. The inhibitory effects of electrical stimulation of either CVAG or SDVAG afferents on the TF reflex are significantly attenuated by either local anesthetic block of the NTS or soma-selective destruction of the NTS61,67,‘0’. Similarly, the behavioral antinociceptive effects of either i.v. morphine or i.v. DALA are significantly attenuated by local anesthesia of the NTS62+67. Finally, ipsilateral, contralateral or bilateral local anesthesia of the NTS significantly attenuates the inhibitor effects of CVAG stimulation on lumbosacral spinal nociceptive transmission76. There are no studies available on the role of the NTS as the initial relay for i.v. serotonin, iv. veratrine, i.v. S-nitrosocysteine or volume-expansion treatments that inhibit spinal nociceptive reflexes by activation of vagal afferents. Studies of the NTS as the initial relay for vagally mediated nociceptive effects are complemented by independent studies of the NTS and its role in the m~ulation of nociception. Electrical stimulation in the NTS or microinjection of glutamate into the NT!3 has been shown to inhibit the TF reflex’,4T40,53,68 and heatevoked responses of lumbosacral spinal dorsal horn neurons18,76. Inhibition of the TF reflex by electrical stimulation in the NTS, like CVAG stimulation, is intensity-, frequency- and pulse-width dependent4. Electrical stimulation in the lateral regions of the NTS are more efficacious than in the medial regions, but there are no apparent differences in NTS-produced antinociception as a function of the rostra]-caudal extent studied (-0.5 mm to 1.5 mm rostra1 to calamus s~riptorius).

The studies of the effects of electrical stimulation in the NTS on heat-evoked responses of lumbosacral neurons by Ren, Randich and Gebhart76 are particularly interesting when compared to vagal influences. Using the same criteria as their CVAG stimulation studies, they found that 78% of the sample was only inhibited (INHIB units) and 22% of the sample was biphasically modulated (BIPHASIC units) by electrical stimulation in the NTS. For INHIB units, there were no differences between ipsiiateral and ~ontralateral NTS stimulation sites in the threshold currents required to produce inhibition, the currents required to inhibit the unit responses to 50% of control values or the latencies to inhibition during noxious heating of the foot. The apparent latency for inhibition, as determined by a CUSUM technique, was approximately 50 ms. Similar to CVAG stimulation, the response threshold to heating of the skin was unaffected by electrical stimulation in the NTS, whereas the slope of the SRF was significantly decreased, The greater percentage of units only inhibited by electrical stimulation of the NTS compared to CVAG stimulation can be accounted for. Specificaliy, since facilitation of spinal dorsal horn units is observed with only low intensities of CVAG stimulation, it is reasonable to assume that only a select subset of vagal afferents is activated under these conditions. The selectivity obtained with stimulation of the vagus is lost with either direct electrical or chemical stimulation of the NTS, revealing the predominate inhibition. Facilitation of unit responses to heat is rarely observed with direct electrical stimulation in the NTS and when seen, occurs at low stimulation intensities in the NTS ipsilateral to the stimulated vagus. Microinjection of glutamate into the ipsilateral NTS results in 81% of units being inhibited and only 9% showing facilitation during noxious heating of the foot68. The inhibitory effects are dose-dependent (lo50 nmol). It is generally held that the NTS has few direct projections to the lumbar spinal cord. In addition, the relatively long latencies required for either facilitation or inhibition of lumbosacral spinal dorsal horn neurons following electrical stimulation of CVAG afferents and information derived from the following studies indicate that input from vagal afferents terminating in the NTS is relayed to other CNS regions to produce antinociception in the rat. The following sections consider various regions that have been investigated to date. 4.2. Nucleus raphe magnus The nucleus raphe magnus (NRM~ has been established in independent studies as a critical relay for

many antinociceptive treatments. Electrical stimulation, microinjection of glutamate or microinjection of morphine into the NRM results in inhibition of spinal nociceptive reflexes and spinal nociceptive transmission’7~2433”~“4387. The NRM also receives direct substance P- and enkephalin-containing projections from the NTS9 and sends substance P- and serotonin-containing projections to the NTS95. Microinjections of either lidocaine61,7” or ibotenic medulla acid 67.77,10’ into the rostra1 ventromedial (RVM), primarily the NRM, attenuate the inhibitory

or,/ 12.

effects of electrical stimulation of either CVAG or SDVAG afferents with respect to both the TF reflex and/or lumbosacral spinal nociceptive transmission. i.v. morphine-produced inhibition of the TF reflex is also significantly antagonized by either lidocaine or ibotenic acid microinjections into the RVM, primarily the NRM’l. On the other hand, i.v. DALA-induced antinociception is unaffected by lidocaine microinjections into either the NRM or the combined NRMlateral reticular formation ‘* . This difference in the effectiveness of the inactivation of NRM with respect

OFF

CE_.

HEATj

7

HEATi

CELi

TIME

( s

)

HEATJ

81

IO Jut VAS i

6

i G 2 a 2

0 0

10

20 TIME

30

( s

40

)

HEAT

7

___

40 @

VA5

8

2’

?6 B In + a z

4 2

y L? z

0

2

0 0

10

20 TIME

120 F

30 ( s

40

50

TIME

)

VAS

(

s

)

VAS

I1--: - 175 pA

El00 s g

80

4 Z

30 m

60

3 40

0

10

20 TIME

30 ( S

)

40

50

0

10

20 TIME

30

40

50

( s )

Fig. 9. An example of CVAG-modulation of an ON and an OFF cell of the RVM. Peristimulus-time histograms (1 s bin width) of responses of an ON cell (left panels) and an OFF cell (right panels) during noxious heating of the tail in the presence and absence of CVAG stimulation,(2 ms, 20 Hz). The upper panels present control data showing the typical ON- and OFF-responses of these cells to noxious he.atmg of the tad. The second panels present lesser intensities of CVAG stimulation that inhibited the ON cell, excited the OFF cell and facmtated the TF reflex relative to all control trials (not shown). The third panels present greater intensities of CVAG stimulation that excited the ON cell, inhibited the OFF cell, and inhibited the TF reflex to the cut-off latency of 10 s. In the second and third panels, the solid bars denote the onset of CVAG stimulation (lower bar) and heat (upper bar) and the arrow indicates the occurrence of the TF reflex. The fourth panel shows corresponding changes in arterial blood pressure during CVAG stimulation. Data are from’m.

91 morphine- and i.v. DALA-produced antinociception is difficult to reconcile, if one assumes that both drugs are operating peripherally on vagal p-receptors to produce antinociception. It is also noteworthy that Ammons et a1.7 showed that electrical stimulation in the NRM inhibited 100% of 42 thoracic spinothalamic tract neurons studied. This is important because 68% of these cells also increased their discharge rate to intracardiac injections of bradykinin and stimulation in the NRM inhibited this increase in 100% of the units. Since these authors previously showed that 100% of thoracic spinothalamic tract neurons responding to intracardiac bradykinin were also inhibited by CVAG stimulation, it is reasonable to assume that the NRM may serve as a CNS relay for CVAG afferent modulation of thoracic spinothalamic cells in the primate. It is also possible to study more detailed aspects of CVAG modulation of cells in the NRM and their role in nociception. Fields and colleagues have classified cells in the NRM of rats based on both their response to noxious heat applied to the tail and the to i.v.

ON

A

occurrence/non-occurrence of the TF reflex20,102,103. ON cells increase their rate of firing immediately preceding the onset of the TF reflex, OFF cells decrease their rate of firing immediately prior to the onset of the TF reflex and NEUTRAL cells show no apparent responses to noxious heat stimulation. Further, these investigators have shown that treatments such as systemic morphine administration not only produce antinociception, but also inhibit the ON-response of ON cells, inhibit the OFF-response of OFF cells and have no effect on NEUTRAL cells. On the basis of this and other information2’, it was proposed that ON and OFF cells control the occurrence of the TF reflex by providing spinopetal modulation of sensory transmission in the spinal dorsal horn. Thurston and Randichloo recorded from 25 ON cells, 18 OFF cells and 68 NEUTRAL cells in the NRM and surrounding regions during electrical stimulation of CVAG afferents and tests of the TF reflex. One would expect that electrical stimulation of CVAG afferents at intensities that inhibit the TF reflex would prevent both the OFF-response of OFF cells and the

CELL

110

851

105 100 95 90 0

3

6

9

12

15

15

Vagal afferent modulation of nociception.

Chemical, electrical or physiological activation of cardiopulmonary vagal (cervical, thoracic or cardiac), diaphragmatic vagal (DVAG) or subdiaphragma...
3MB Sizes 0 Downloads 0 Views