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NOCICEPTIVE MODULATORY CIRCUITS Howard

L.

Fields, Mary M. Heinricher, and Peggy Mason

Departments of Physiology and Neurology, University of California School of Medicine, San Francisco, California 94143 KEY WORDS:

pain, analgesia, endogenous opioid peptide, serotonin, norepi­ nephrine, GABA

The mammalian central nervous system possesses well-defined networks that modulate nociceptive transmission. The most extensively studied are the networks that underlie brainstem control of nociception in the spinal cord dorsal horn. Two brains tern sites from which major projections to the dorsal horn originate have been identified: the rostral ventromedial med ulla (RVM), which is the focus of this review, and the dorsolateral pontine tegmentum. The significance for pain modulation of the afferent projection from the midbrain to the RVM and from the RVM to the dorsal horn has been established by multiple lines of evidence (see Basbaum & Fields 1984, Besson & Chaouch 1987). The nociceptive modulating action of this pathway involves a variety of neurotransmitters within the RVM itself, including serotonin (SHT), enkephalin, GABA, norepinephrine (NE), neurotensin and excitatory amino acids (EAA). In this review we emphasize the roles of each of these neurotransmitters within the RVM and in the dorsal horn region where the axons of RVM neurons terminate. ANATOMY OF RVM: AFFERENT CONNECTIONS AND PROJECTIONS TO THE DORSAL HORN

The RVM includes the nucleus raphe magnus and adjacent ventral reticu­ lar formation. In the cat the adjacent reticular area is roughly cbextensive with the n. reticularis magnocellularis (Taber et aI196l}. The rostrocaudal extent of the RVM is approximately from the caudal pole of the facial 219 0147-006Xj9lj030I-02l9$02.00

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nucleus to the level of the trapezoid body. In the rat, the RVM includes the n. raphe magnus, n. reticularis gigantocellularis pars alpha, and n. reticularis paragigantocellularis lateralis over a similar rostrocaudal extent (Basbaum & Fields 1984). The midbrain periaqueductal gray (PAG) and adjacent n. cuneiformis constitute a major afferent input to the RVM (Mantyh & Peschanski 1982, Beitz 1982a, Marchand & Hagino 1983), and there is an extensive body of evidence demonstrating that the RVM serves as a relay for midbrain modulatory influences upon spinal nociceptive transmission (Fields & Basbaum 1978, Basbaum & Fields 1984). Thus, the inhibition of behavioral and dorsal horn neuronal responses to noxious stimulation produced by electrical or chemical activation of PAG can be blocked by lesions of or local anesthetic injection into the RVM (Gebhart et al 1983, Sandkuhler & Gebhart 1984a, Prieto et al 1983, Chung et al 1987). The RVM also receives a significant input from neurons in the dorsally adjacent medullary reticular formation (Maciewicz et al 1984, Mason et al 1986, Abols & Basbaum 1981) and the dorsolateral pontine tegmentum, another area implicated in nociceptive modulation (Giradot et a11987, Haws et a1 1989, Holstege 1988). Other inputs to the RVM arise from diencephalic and telencephalic structures, including the hypothalamus, the frontal cortex, the amygdala, and the bed nucleus of the stria terminalis (Hoistege 1987). Although the RVM projects to several brainstem and spinal cord sites, its major descending projections are to the spinal and trigeminal dorsal horns (Basbaum et al 1978, Holstege & Kuypers 1982, Mason & Fields 1989, Bobillier et al 1976, Skagerberg & Bjorklund 1985). Axons of RVM neurons terminate densely in laminae I, II, and V of the trigeminal nucleus caudalis and project via the spinal dorsolateral funiculus (DLF) to ter­ minate in laminae I, II, V, VI, and VII of the spinal dorsal horn (Basbaum et al 1978, 1986a, Basbaum & Fields 1979, Ruda et al 1981, Holstege & Kuypers 1982). These laminae are known to contain the terminals of small­ diameter nociceptive primary afferents (Cervero & Iggo 1980, Light & Perl 1979a,b) as well as neurons that respond to noxious stimuli and project to the brainstem and thalamus (Fields & Basbaum 1978, Dubner & Bennett 1983). Single RVM axons collateralize and terminate in the dorsal horn bilater­ ally at multiple levels of the spinal cord and in the sensory trigeminal complex (Martin et al 1981, Skagerberg & Bjorklund 1985, Huisman et al 198 1). Furthermore, the terminal fields of DLF axons that are ortho­ dromically activated by RVM micro stimulation are oriented transversely in the dorsal horn and thus extend across somatotopic boundaries (Light 1985). This widely collateralized, yet lamina-specific projection pattern is consistent with behavioral and physiological evidence that RVM neurons >

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exert a topographically diffuse modulatory action predominantly upon nociceptive transmission. ON- AND OFF-CELLS: NOCICEPTIVE

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MODULATORY NEURONS IN THE RVM

Three physiologically distinct classes of neurons can be identified in the RVM based upon the temporal correlation of changes in their firing with the execution of nocifensor reflexes elicited by noxious stimulation (Fields et al 1988). For example, when the tail flick reflex is elicited by noxious heat in a lightly anesthetized rat, the three classes display distinct changes in firing. Cells of one class, termed "on-cells," reliably show a sudden increase in firing rate just prior to the occurrence of the tail flick. On-cells are maximally activated by stimulation sufficient to evoke a withdrawal reflex. Such stimulation is generally effective when applied anywhere on the body surface. A significant number of on-cells are also excited, albeit weakly, by innocuous mechanical stimulation. Cells of a second class, "off-cells," are characterized by an abrupt pause in firing that begins approximately 400 ms prior to the TF response. Although noxious stimu­ lation anywhere on the body surface can elicit a pause in firing, non­ noxious stimulation is usually ineffective. Finally, cells that display no change in firing related to the execution of the TF response are termed "neutral cells." In addition to the nocifensor reflex-related changes in their firing pattern, other evidence indicates that on- and off-cells play a central role in descend­ ing nociceptive modulation. Both cell classes are excited by electrical stimulation in the PAG at a current just sufficient to inhibit the tail flick (Vanegas et al 1984b). Furthermore, a significant proportion of each cell class can be antidromically activated from the spinal cord (Vanegas et al 1984a). The spinal target of on- and off-cell terminals is likely to be the dorsal horn, as this is the major spinal projection from the RVM as a whole. The recent observation that intracellulariy labeled axons of on- and off-cells can be followed to the trigeminal sensory complex supports this conclusion (Mason & Fields 1989). Additional evidence indicating that both on- and off-cells modulate nociceptive transmission comes from electrophysiological studies. In rats maintained under light barbiturate anesthesia, and in the absence of imposed cutaneous stimulation, the ongoing discharge of both on- and off-cells spontaneously alternates between periods of relatively high firing rate and periods of silence, or more rarely, very low activity (less than 1 Hz) (Barbaro et al 1989). These alternating periods of silence and activity are of variable duration, averaging about 80 s. Simultaneous recordings

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from pairs of the RVM neurons under these conditions indicate that all neurons of the same class are active during the same periods, whereas neurons of the other class are active during the alternate periods. Measure­ ments of nociceptive responsiveness made as the two cell classes alternate between periods of activity and silence demonstrate a correlation between cell activity and TF latency: The tail flick threshold is significantly higher during periods of off-cell activity (and thus on-cell silence) and lower during period of off-cell silence (and on-cell firing) (Heinricher et aI1989). These correlative results are evidence that each class of presumed nocicep­ tive modulatory neurons in the RVM, acting as an integrated population, is involved in the modulation of nociception.

The Role of the Off-Cell: Suppression of Nociceptive Transmission If the off-cell were to exert a net inhibitory effect on nociceptive trans­ mission, a pause in its firing would disinhibit dorsal horn neurons, thereby permitting nociceptive transmission and execution of nocifensor reflexes. In fact, the onset of the off-cell pause precedes both the occurrence of withdrawal reflexes (Fields et al 1983a) the onset of and the response of thalamic neurons to noxious stimulation (Hernandez et al 1989). Further­ more, the TF occurs wi th a shorter latency if ,the onset of the off-cell pause is advanced by noxious stimulation applied at a distant body site, such as the tooth pulp, just prior to noxious heating of the tail (Ramirez & Vanegas 1989). Perhaps the most compelling evidence that off-cells inhibit nociceptive transmission is the observation that all off-cells, but no other RVM neurons, become continuously active following administration of mor­ phine either systemically (Fields et al 1983b) or by microinjection into the PAG (Cheng et a11986) in doses sufficient to inhibit the TF. The opiate activation of off-cells is particularly significant because of the evidence that the modulatory output neuron in the RVM responsible for nocifensor reflex suppression is excited by opiates. Thus, activation of RVM neurons by electrical stimulation in RVM results in TF suppression (Oliveras et al 1975, Sandkuhler & Gebhart 1984b, Zorman et al 1981), whereas inac­ tivation of RVM neurons or a lesion of their projection to the spinal cord does not (Proudfit 1980, 1981, Barton et a11980, Kaplan & Fields 1990). Furthermore, morphine and the neurocxcitant I-glutamate both produce antinociception when microinjected at the same RVM sites (Jensen & Yaksh 1989). Thus, since morphine administration consistently and selec­ tively activates off-cells, and since inhibition of nocifensive reflexes requires activation of an R VM output neuron, the off-cell must have a net inhibitory effect on such reflexes.

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On-Cell: Evidence for Facilitation of Nociception Several lines of evidence suggest that on-cells exert a permissive or even facilitating action on nociceptive transmission. That on-cells are highly active just prior to and during execution of the tail flick response indicates that on-cell firing does not have a potent inhibitory action on nocifensive reflexes. Moreover, administration of morphine suppresses on-cell firing (Barbaro et al 1986, Cheng et al 1986). Nonetheless, it has been difficult to establish that there is a separable facilitating output from the RVM. On- and off-cells are intermixed and distributed throughout the RVM, and the two populations tend to fire reciprocally under most conditions. Thus, any observed enhancement of nociception that is correlated with an increase in on-cell activ ity could be explained as due to removal of descend­ ing inhibition exerted by off-cells. We have been able to address this problem by studying rats in the period following reversal of morphine's antinociceptive action by the opiate antagonist naloxone. During this period, there is a significant enhancement of nociceptive responsiveness (i . e . a decrease in tail flick latency compared to the prcmorphine baselinc) (Jacob et aI1974). This enhanced nociceptive responsiveness is associated with a high rate ofRVM on-cell firing (Beder­ son et al 1990) and can be attenuated or reversed by microinjection of a local anesthetic into the RVM (Kaplan & Fields 1990). These observations demonstrate that the decrease in tail flick latency following administration of naloxone involves the activation of an RVM output neuron that facili­ tates nociception, rather than merely removal of a descending inhibitory effect. Clearly , this active facilitation is likely a function of on-cell act ivity , as this is the only RVM neuron known to be activated under these conditions. In summary, two physiologically distinct classes of RVM neurons pro­ ject to the dorsal horn, where they are likely to exert opposing actions on nociceptive transmission. Thus, modulation of nociception by the RVM must be interpreted in terms of the interactions of these two populations within the RVM and at their terminations in the dorsal horn. RVM CIRCUITRY: RELATIONSHIP TO NOCICEPTIVE MODULATION

Our knowledge of RVM circuitry is by no means certain or complete. Clearly, it suffers from a lack of direct proof of the physiological identity of cells containing specific transmitters. Nonetheless, multiple converging lines of evidence make the presence of certain connections and putative neurotransmitters probable. Furthermore, there is a sufficient accumu-

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lation of evidence to propose a model that may be of heuristic value (Figure 1). The experiments described above using simultaneous recordings from pairs of on-cells and off-cells demonstrated physiologically significant inte­ gration among the putative nociceptive modulating neurons in the RVM. This observation suggested that any connections within either cell class were likely to be excitatory, whereas connections between the two classes were likely to be inhibitory. Recent studies in which the axons of intracellularly labeled on- and off­ cells were traced within the lower brainstem of the cat suggest an ana-

PAG

EAA

RVM

DORSAL HORN NET EFFECT

t

t

t

Figure 1 A summary of the hypothesized connections discussed in the text. Neurons in PAG that contain excitatory amino acids (EAA) project to the RVM and excite off-cells (off) that have a net inhihitory effect on nociceptive transmission in the dorsal horn. Off­ cells, some of which likely contain 5HT, and some of which do not, have extensive axonal projections within the RVM. The off-cells' connections are likely to be excitatory to other off-cells and inhibitory to RVM on-cells. On-cells project to the dorsal horn, where they have a net facilitating effect on nociceptive transmission. On-cells are directly inhibited by enkephalin containing cells (enk). Some of the on-cells that are inhihited by opioid peptides probably contain GABA and have localized axonal collaterals that may inhibit off-cells. This circuit provides for opiate disinhibition of off-cells. Extrinsic neurons that contain 5HT, neurotensin (NT), and norepinephrine (NE) all project to the RVM. The effects of 5HT and NT afferents from the PAG on RVM on- and off-cells are unknown. NE evokes both an excitation that is at ,-mediated and an inhibition that is at2-mediated in on-cells.

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tomical substrate within the RVM for coordinating the activity of the two populations (Mason & Fields 1989). The axons of intracellularly labeled off-cells were found to project densely throughout RVM. In contrast, although a subset of on-cells had axons with limited terminations within the dendritic arbor of the parent cell, most on-cells showed no axonal collaterals or swellings within the RVM itself. These findings suggest that off-cells play a major role in the integration of activity throughout the RVM, exciting other off-cells, inhibiting on-cells, or both. On-cells may have a more limited role providing highly localized connections to neigh­ boring RVM neurons. Extensive, mutually excitatory connections among widely separated off­ cells, but not among on-cells, within the RVM could provide an anatomical basis for the predominantly antinociceptive effect that is observed with electrical stimulation anywhere in the RVM. By such connections, elec­ trically evoked activation of a small number of off-cells could result in widespread recruitment of other off-cells throughout RVM. The concept of recruitment by active off-cells of other off-cells is supported by the finding that the threshold current in RVM for electrical micro stimulation to inhibit the tail flick is significantly lower when the electrode is near a single RVM off-cell than when it is near an on-cell or neutral cell (Barbaro et al 1987). In contrast, because of the paucity of interconnections, the direct activation of a small number of on-cells by local electrical stimu­ lation would presumably have limited effects on other on-cells. Thus, in the basic model of intrinsic RVM circuitry that we currently favor, off-cells excite other off-cells and inhibit on-cells throughout the RVM. Some on-cells are proposed to inhibit neighboring off-cells. In addition, some on-cells may excite neighboring on-cells. Such local con­ nections may be involved in the generation of the off-cell pause and the on-cell burst and in the cyclic pattern of spontaneous firing displayed by both cell classes. Extrinsic afferents to the RVM may also contribute to the coordination of on- and off-cell activity. In the next sections, some neurotransmitters potentially involved in several of these proposed syn­ apses are considered.

The Off-Cell Pause: GABA-mediated Inhibition Anatomical, behavioral, and physiological studies indicate that activation of a GABA-containing input is responsible for the off-cell pause. Cell bodies and terminals containing GABA are abundant in the RVM (Millhorn et a1 1988 , GABAA and GABAB binding sites have been demonstrated in the region (Bowery et aI1987). Significantly, pharmacological interventions directed at GABA-mediated synaptic transmission within the RVM profoundly

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alter nociceptive responsiveness: Blockade of GABAA receptor-mediated inhibitory processes by microinjection of GABAA receptor antagonists is antinociceptive, whereas application of selective GABAA receptor agonists in the RVM facilitates responses to nociceptive stimulation (Drower & Hammond 1988, Heinricher & Kaplan 1989). Interestingly, although GABAB binding sites are relatively dense in the RVM, microinjection of baclofen, the prototypical GABAB agonist, is apparently without effect on nociception (Levy & Proudfit 1979). Observations such as these clearly indicate that GABA-mediated inhibi­ tory processes control modulatory output from the RVM, and provide significant clues about where GABA might act within the RVM circuitry. Given that the off-cell pause removes a major inhibitory influence acting upon nociceptive transmission and nocifensi ve reflexes, the effects of direct application of GABAA receptor agonists and antagonists in the RVM suggest that the reflex-related off-cell pause is due to activation of a GABA­ containing input to the off-cell. Consistent with this, the off-cell pause induced by tail heating is abolished by iontophoretic application of the GABAA receptor antagonist, bicuculline methiodide (Heinricher et al 1987), and at the ultrastructural level, GABA-containing terminals have been shown to make contact with physiologically characterized, intra­ cellularly labeled off-cells (Mason et al 1990). One implication of the above evidence is that, if the GABA-mediated input responsible for the pause arises from neurons intrinsic to the RVM, those neurons would, on physiological grounds, be classified as on-cells (Figure 1). That is, the GABA-containing interneurons would be expected to show a burst of activity beginning just before the occurrence of the TF, at the time of the off-cell pause. The observed reciprocal pattern of on­ and off-cell spontaneous activity is consistcnt with this idca, and the local axon collaterals of a subset of on-cells provide a possible substrate for a GABA-containing input to off-cells from on-cells. Furthermore, noxious peripheral stimulation, which would be expected to activate on-cells, has been shown to increase GABA release into the fourth ventricle (Ge et al 1988). It is possible that the GABA-containing cells that mediate the off-cell pause are not intrinsic to the RVM. However, little is known about GABA­ ergic projections to RVM. It is known that very few PAG neurons that project to RVM contain GABA (Reichling et al 1988b).

Opioid Activation of Off-Cells Autoradiographic studies have demonstrated mu opiate binding sites in the RVM (Bowker & Dilts 1988) and microinjcction of morphine or opioid peptides into the RVM has an antinociceptive effect (Azami et al 1982,

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Dickenson et a1 1979, Jensen & Yaksh 1986a, Levy & Proudfit 1979). Because the direct cellular actions of opioid receptor agonists are generally inhibitory (Duggan & North 1984, Nicoll et al 1980), opioid excitation of off-cells is most likely due to disinhibition (Fields et al 1983b). Our recent studies are consistent with this hypothesis. Iontophoretically applied mor­ phine has an inhibitory effect on RVM on-cells, but no effect on off-cells could be demonstrated (Heinricher et al 1990). If, as discussed in the previous section, GABA mediates the RVM off-cell pause, it is not unreasonable to suggest that a subset of RVM on-cells are GABAergic inhibitory interneurons. Recent evidence consistent with this suggestion was provided by intracellular recordings from uncharacterized RVM cells in a medullary slice preparation (Pan & Williams 1990). In this study, bath-applied opioids depressed GABA-mediated IPSPs in one popula­ tion of RVM neurons but had no direct post-synaptic action on those cells. A second subset of medullary neurons (possibly GABA-ergic) was found to be directly hyperpolarized by opiates acting at a mu opioid receptor. These electrophysical data are consistent with the hypothesis that opioid inhibition of a GABA-mediated inhibitory process involves postsynaptic inhibition of an intrinsic GABA-containing interneuron (with the prop­ erties of an on-cell). Further support for this proposed mechanism is that very few GABA-containing axo-axonic synapses are found in the RVM (Reichling et al 1988a), so there is little, if any, anatomical substrate for presynaptic inhibition. Enkephalin-immunoreactive terminals and cell somata are concentrated in the RVM (Hunt & Lovick 1982, Bowker et al 1988, Menetrey & Bas­ baum 1987). This region also contains dynorphin-immunoreactive ter­ minals, but dynorphin-positive somata are restricted to more lateral regions of the RVM and thus are not coextensive with pain-modulating areas. Extrinsic sources of enkephalin terminals in the RVM include the PAG, the locus coeruleus and the nucleus subcoeruleus (Luppi et a1 1988, Beitz 1982b). That enkephalin, released from local terminals in the RVM, plays a role in nociceptive modulation is supported by the observation that enkephalinase inhibitors microinjected into the RVM have a naloxone­ reversible antinociceptive effect (AI-Rodhan et aI 1990). Finally, consistent with the hypothesis that opioids activate off-cells indirectly, enkephalin­ immunoreactive axonal swellings have been demonstrated to be apposed to intracellularly labeled RVM on-cells (Back et a1 1990).

Serotonin: An Off-Cell Neurotransmitter? A significant number of RVM neurons, including many that project to the spinal cord, contain 5HT (Bowker et al 1981, 1983, Lovick & Robinson

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1983, Skagerberg & Bjorklund 1985). In fact, the RVM is the major source of dorsal horn 5HT (Dahlstrom & Fuxe 1964, Oliveras et aI1977). Depletion of spinal cord 5HT by the neurotoxin 5,7-dihydroxytryptamine blocks the antinociceptive effect of morphine microinjected into RVM (Vasko et al 1984). Supraspinal opioid microinjection evokes release of 5HT in the spinal cord (Yaksh & Tyce 1979). Since off-cells are the only RVM neurons activated by opioid administration, these data indicate that at least a subset of off-cells contain 5HT. This concept is also sup­ ported by the observation that systemic morphine increases the con­ centration of 5HT metabolites in the RVM (Rivot et a1 1988, 1989), and that microinjection of a 5HT neurotoxin into RVM reduces the antinociceptive action of morphine (Mohrland & Gebhart 1980). It should be pointed out that these data do not bear on the issue of whether all 5HT-containing RVM neurons are off-cells. Serotonin may participate in local interactions among off-cells. Micro­ injection of 5HT into the RVM has an antinociceptive action (Llewelyn et al 1983, Inase et al 1987, but see Aimone & Gebhart 1986), and drugs that release 5HT or block its reuptake have the same antinociceptive effect (Llewelyn et al 1984). This result, and the observation that local microinjection of the 5HT antagonist, methysergide, into the RVM raises the local electrical threshold for inhibiting the TF response (Aimone & Gebhart 1986) suggest that at least a subset of off-cells are excited by local 5HT release. Iontophoretic studies of the effect of 5HT on uncharacterized RVM neurons have revealed two types of responses. One group of cells was reported to be excited by 5HT, an effect mediated through a 5HT 2 receptor (Davies et aI1988a). A second group of cells was inhibited by iontophoretic application of 5HT, possibly by an action at a 5HT I-like receptor (Davies et aI1988b). That 5HT can exert opposing actions on the firing of different classes of RVM neurons is particularly intriguing, as it raises the possibility that individual off-cell axons releasing 5HT could simultaneously activate other off-cells and inhibit on-cells (Figure 1). Either or both of these actions could contribute to the antinociceptive effect of local application of 5HT within the RVM. There are significant extrinsic sources of 5HT -containing terminals in the RVM, including neurons in the periaqueductal gray and the midbrain B8 and B9 cell groups (Beitz 1982a, Beitz et al 1983). Thc functional significance of the serotonergic projection from midbrain to the RVM is unclear. The antinociception produced by PAG stimulation may not require an action of 5HT within the RVM, as it is reportedly not blocked by microinjection of 5HT-receptor antagonists into the RVM (Aimone & Gebhart 1986).

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Excitatory Amino Acids: Role in the Relay from the PAG to the RVM Electrical stimulation in the PAG evokes a short latency excitation in many RVM neurons (Mason et al 1985, 1986, Pomeroy & Behbehani 1979), including identified on- and off-cells (Vanegas et alI984a). Evidence that this effect is mediated at least in part by PAG neurons that project to the RVM and utilize excitatory amino acids (EAAs) as a transmitter has recently been provided via several approaches. Although there may be other sources for the EAA-containing terminals in the RVM, neurons immunoreactive for both glutamate and aspartate are present throughout the PAG (Clements et aI1987), and a subset projects to the RVM (Wiklund et al 1988). In electrophysiological experiments, short-latency responses evoked in RVM neurons by PAG stimulation were, in many cases, reduced by iontophoretic application of the nonselective EAA antagonists kynur­ enatc and O:-D-glutamylglycine. Sclective NMDA receptor antagonists were ineffective (Wiklund et al 1988). Using a behavioral approach, Aimone & Gebhart (1986) were able to demonstrate a functional role for the EAA pro­ jection from the PAG to the RVM in nociceptive modulation: Microinjection of nonselective EAA receptor antagonists into the RVM significantly in­ creased the PAG-stimulating current required to inhibit the TF. Since the threshold for electrical stimulation in the PAG to excite off-cells is the same as that for inhibition of the TF, it is likely that the EAA-containing affer­ ents from PAG produce antinociception by exciting RVM off-cells.

Neurotensin: Another Transmitter in the Pathway from the PAG to the RVM Neurons containing the tridecapeptide neurotensin constitute a major component of the projection from the ventrolateral part of the PAG to the RVM (Beitz 1982a, Beitz et al 1983). Neurotensin-binding sites have been localized to the RVM (Quirion et al 1982, Young & Kuhar 1981), and microinjection of neurotensin in the RVM produces a dose-related suppression of the tail flick (Fang et al1987). Thus, both behavioral and anatomical evidence suggest that neurotensin is involved in the nociceptive­ modulatory influence of the PAG on the RVM.

Norepinephrine: Modulation of On-cell Activity In addition to its direct action at spinal levels (see below), NE influences nociceptive modulatory neurons in the RVM. NE-containing fibers and terminals are present throughout the RVM (Fuxe 1965, Takagi et aI198 l ), and both 0:1- and aradrenergic binding sites have been identified there (Young & Kuhar 1980, Unnerstall et aI1984). Moreover, manipulation of

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noradrenergic transmission within the R VM affects its nociceptive modu­ latory function (Hammond et al 1980, Sagen & Proudfit 1985). Micro­ injection of the IXTadrenergic agonist clonidine produces an increase in TF latency. In contrast, microinjection of the lXI-adrenergic agonist phenyl­ ephrine results in either a decrease in tail flick latency (in awake rats) or no effect (in lightly anesthetized rats) (M. M. Heinricher and C. M. Haws, in press). At the single neuron level, both inhibitory and excitatory effects of iontophoretic application of NE have been observed, although the effect on identified raphespinal neurons has been reported to be predominantl y inhibitory (Behbehani et a1 1981, Wessendorf & Anderson1983, Willcock­ son et al 1983). In recent experiments in lightly anesthetized rats, we determined that on-cells but neither off- nor neutral-cells respond to iontophoresis of agents acting at IX-adrenergic receptors (Heinricher et al 1988). Iontophoresis of NE itself produced a relatively short-lasting (6090 s) iY.1-mediated increase in on-cell spontaneous activity, as demonstrated by the fact that the effect was blocked by prazosin but not yohimbine. This finding is consistent with the enhancement of nociceptive reflexes seen in awake rats following microinjection of an lXI-adrenergic agonist in the RVM. The lack of effect of such microinjections in anesthetized rats may be due to the relatively short time-course of the iY.j-receptor-mediated on­ cell excitation in such animals. In contrast, iontophoretic application of clonidine, which produces antinociception when microinjected into the RVM in both awake and anesthetized animals, resulted in a long-lasting (10-30 min) inhibition of on-cell firing, presumably mediated by an action at an iY.radrenergic receptor. These experiments are wholly consistent with the idea that on-cells exert a permissive or facilitating effect on nociceptive transmission r The noradrenergic input to the RVM appears to derive, at least in part, from the regions that include A5 and A7 in the pons (Kwiat & Basbaum, in press). There may also be a contribution from the A l catecholamine cell group in the ventrolateral medulla (Takagi et al 1981, Dong & Shen 1986). Neurons in each of these areas have been implicated in nociceptive modulation. Electrical stimulation in the area of A 7, the rostral part of AS, or in A l produces antinociccption and inhibition of dorsal horn neurons (Proudfit 1988). Lesions of the caudal portion of A5 also increase TF latency (Sagen & Proudfit 1986). Unfortunately, electrical stimulation and structural lesions in these regions do not affect catecholaminergic neurons selectively. Clearly, the relationships between the RVM and neurons in each NE-containing cell group nccd to bc dctailed for an understanding of the contribution of NE to control of nociceptive modu­ latory neurons in the RVM. .

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INHIBITORY CIRCUITRY AT THE LEVEL OF THE DORSAL HORN

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Serotoninergic and Noradrenergic Input to the Spinal Cord A large body of pharmacological evidence supports a role for spinally released 5HT in the RVM-mediated modulation of nociceptive trans­ mission (see Anderson & Proudfit 1981, Basbaum & Fields 1984, Roberts 1988, Yaksh 1985). Intrathecally administered 5HT raises the threshold of a variety of nocifensor reflexes in cat, rat, and rabbit-effects that are potentiated by monoamine oxidase (MAO) inhibitors and by 5HT agonists and precursors, and are attenuated by SHT receptor antagonists (Yaksh & Wilson 1979, Schmauss et al 1983). TF suppression produced by elec­ trical stimulation (Hammond & Yaksh 1984, Barbaro et a1 1985) or opiate microinjection (Jensen & Yaksh 1986b) in the RVM is reduced by intra­ thecal administration of the SHT antagonist methysergide, evidence that 5HT release contributes to the antinociception produced by activation of RVM neurons. Different 5HT receptor subtypes may be involved in the brainstem control of different dorsal horn neuronal populations. At least four types of SHT receptors are thought to be present in the spinal cord: SHTIA, 5HTIB, a new 5HT 1 SUbtype [5HT1S (Zemlan et al 1989a, Schwab et al 1989, Murphy et aI1989)], and SHT3 (Waeber et aI1989). The SHT1A and SHT 3 receptors appear to be localized, at least in part, on primary afferent terminals (Daval et al1987, Hamon et al 1989). 5HT, receptors are clearly involved in the inhibition of nociceptive dorsal horn neurons by NRM stimulation (EI-Yassir & Fleetwood-Walker 1990). There is conflicting evidence about the behavioral actions of ligands at the SHTI-receptor SUbtypes. For instance, the intrathecal administration of 8-0H-DPAT, a 5HT'A agonist, was reported to either decrease TF latency (Solomon & Gebhart 1988) or to have no effect (Fasmer et al 1986). In addition, in some cases the investigator has reported mixed effects of both 5HT lA and 5HTIB agonists on different nocifensive reflexes (Fasmer et al 1986, Zieleniewski et al1989). As an example, both 5HT lA and SHT IB agonists increase responsiveness in a reflex evoked by noxious mechanical stimulation and decrease responsiveness in a test of thermal nociceptive transmission (Zieleniewski et al1989). Systemic administration of certain 5HT, agonists suppresses the TF in spinalized rats, although the effect of 5HT 1 agonists on single neurons is unclear (Schwab et al 1989). The electrophysiological data on SHT 1 receptor subtype effects is more limited and less controversial. Iontophoresis of 5HT inhibits the nocicep­ tive responses of dorsal horn neurons to noxious but not innocuous stimuli through an action at the SHT'B receptor (El Yassir et al 1988). Further-

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more, iontophoresis of mCPP, a selective 5HT1B receptor agonist, inhibits glutamate-evoked activity in lamina V nociceptive neurons that are also inhibited by RVM microstimulation (Zemlan et al 1988). This result is consistent with a 5HT1B-mediated inhibition of projection cells or inter­ neurons. A nonselective inhibition of dorsal horn cells is reported to be mediated by 5HT1A receptors (El Yassir et a1 1988, Zemlan et aI1989b). Recently, 5HT 3 receptors have been localized to primary afferent ter­ minals in lamina II of the dorsal horn (Hamon et al 1989, Waeber et al 1989). A role for spinal 5HT 3 receptors in nociceptive control is indicated by the observations that intrathecal administration of a 5HT rselective antagonist causes "hyperalgesia" and reverses the antinociceptive action of 5HT (Glaum et al 1988). Nonserotonergic mechanisms must also be involved in the control by the RVM of dorsal horn nociceptive transmission, since intrathecally administered methysergide is only partially effective in blocking anti­ nociception from the RVM, and a significant proportion of RVM bulbo­ spinal neurons do not contain 5HT. Indeed, the observed conduction velocities of cord-projecting RVM on- and off-cells are in the range of myelinated axons, whereas almost all serotonergic axons are unmyelinated (Vanegas et al 1984b, Basbaum et aI1988). Pharmacological studies have implicated NE in the control by RVM of nociceptive transmission. Thus, depletion of spinal NE by intrathecal 6OH dopamine markedly attenuates the antinociceptive effect of morphine microinjected into the RVM (Pang & Vasko 1986). Norepinephrine also has well established antinociceptive effects when applied intrathecally (see Proudfit 1988). For example, intrathecal administration of a-adrenergic receptor antagonists blocks opiate analgesia (Proudfit & Hammond 198 1). Iontophoretically applied NE acting through an a2-adrenergic receptor inhibits the firing of nociceptive cells in the dorsal horn, including some projecting to supraspinal sites (Fleetwood-Walker et al 1985, Millar & Williams 1989, Zhao & Duggan 1988). In addition to this inhibitory action on projection neurons, iontophoretically applied NE excites a distinct population of dorsal horn neurons that responds only to innocuous peri­ pheral stimulation. These cells are also excited by electrical stimulation of PAG (Millar & Williams 1989). This latter group of neurons could be local inhibitory interneurons. These results would suggest that NE inhibits nociceptive projection neurons both directly and indirectly, by exciting local inhibitory interneurons (further discussion below). There is evidence that the spinal nociceptive modulatory actions of 5HT and NE are interdependent. When rats are depleted of NE by a selective neurotoxin DSP4, the analgesia produced by MeODMT, a 5HT1S agonist, is blocked. MeODMT analgesia is not blocked by prior 5HT depletion (Archer et aI1985). These results are evidence that an intact noradrenergic

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system at the spinal level is required for 5HT-mediated suppression of nociceptive transmission. The importance of spinal noradrenergic ter­ minals for the pain-modulating actions of 5HT is further supported by the finding that the antinociceptive effects of intrathecal mCPP or MeODMT, agonists at the 5HT 1B and 5HT IS receptors, are blocked by the a-adrenergic antagonists, prazosin and phentolamine, respectively (F. P. Zemlan, per­ sonal communication). In addition to the noradrenergic mediation of serotonergic antinociception, descending serotonergic fibers may influence adrenergic-mediated antinociception, since intrathecal administration of 5HT attenuates the antinociception produced by intrathecal NE (Clat­ worthy et al 1988). If part of the spinal antinociceptive action of 5HT is mediated via a noradrenergic terminal (Figure 2A), then 5HT-containing terminals should contact dorsal horn neurons or NE-containing terminals synapsing onto those neurons. In fact, noradrenergic terminals are found in laminae I, II, and V of the dorsal horn, the same laminae that receive serotonergic terminals from descending RVM axons (Ruda et a1198 l , 1982).

Local Dorsal Horn Circuitry that Underlies Descending Control A picture of the circuitry by which RVM neurons exert their modulatory influence on dorsal horn neurons is beginning to emerge. It should be stressed, however, that although descending control is clearly bidirectional, only those mechanisms underlying inhibition of dorsal horn nociception have been extensively studied. Because the recognition of RVM-mediated facilitation of nociceptive transmission is quite new and little is known of the dorsal circuitry that mediates it, the following discussion deals only with inhibitory dorsal horn mechanisms. RVM axon terminals in the dorsal horn make axosomatic and axoden­ dritic contacts with both thalamic relay cells and local circuit neurons. The rarity in the dorsal horn of axoaxonic synapses from anterograde1y labeled RVM axons or DLF axons (Basbaum et al 1986a, Light & Kavookjian 1985, Ruda et al 1981) indicates that direct effects of RVM neurons at the level of dorsal horn may not involve traditional presynaptic control. It is possible, however, that neuromodulators released from RVM axon terminals in the dorsal horn could act on nearby afferent terminals with which they have no direct synaptic contact. Three possible circuits that include a post-synaptic action on dorsal horn cells by RVM neurons and could account for inhibition of nociceptive transmission will be considered here. The simplest circuit is one in which the terminals of RVM neurons (presumably off-cells) directly inhibit ros­ trally projecting nociceptive relay neurons (Figure 2B). Consistent with

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(A)

(8)

LY!>------'---CP

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(e)

off



SHT I non-SHT

(D)

off

RVM

DORSAL HORN T



+

cp



Figure 2 Possible circuits for RVM inhibition of dorsal horn nociceptive transmission. (A) RVM off-cell axons that contain serotonin exert their inhibitory actions on thalamic pro­ jection neurons through an interaction with norepinephrine (NE)-containing axons that also tenninate in the dorsal horn. The nature of this interaction is unclear. (B) RVM off-cell (off) directly inhibits nociceptive dorsal horn cells that project to the thalamus (T). Some of the off-cells in this circuit probably contain serotonin and some do not. (e) Nociceptive pro­ jection cells receive inputs directly from primary afferents and indirectly from excitatory intcrneurons (E). RVM off-axons act to inhibit the nociccptive projection neuron indirectly through the inhibition of the excitatory interneuron. As above, some of the off-cells in this circuit probably contain serotonin and some do not. (D) Nociceptive transmission cells in the dorsal horn are inhibited by dorsal horn interneurons (I), which may contain enkephalin, GABA, or another transmitter. These inhibitory interneurons are activated by RVM off-cell axons, some of which probably contain serotonin and some of which do not.

this, stimulation of the RVM evokes a monosynaptic IPSP in identified lamina V spinothalamic tract neurons (Giesler et al 1981). Since any serotonergic inputs to dorsal horn neurons are likely to arise from the RVM, the report that spinothalamic tract neurons in the superficial dorsal horn receive numerous synaptic contacts from serotonin-containing fibers would provide anatomical evidence in support of this model (Hylden et al 1986). That iontophoretically applied 5HT inhibits nociceptive spino­ thalamic cells (Jordan et al 1978, Willcockson et al 1984) and that 5HT­ immunoreactive contacts are concentrated on nociceptive dorsal horn cells that are inhibited by electrical stimulation within the RVM (Miletic et al 1984) also supports a direct post-synaptic inhibitory effect upon dorsal horn cells from serotonergic neurons in the RVM. A second possibility is that RVM neurons modulate the activity of nociceptive projection neurons indirectly through an effect on dorsal horn

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interneurons. Indirect modulation of dorsal horn projection cells could occur through inhibition of an excitatory interneuron (Figure 2C) or excitation of an inhibitory interneuron (Figure 2D). In fact, there is evi­ dence that both mechanisms play a role. Intracellularly labeled DLF axons, directly activated by RVM microstimulation, make either symmetric, pre­ sumably inhibitory, or asymmetric, presumably excitatory, axodendritic and axosomatic synapses in laminae I and II (Light 1985, Light & Kavook­ jian 1985). These same laminae contain interneurons that connect with projection neurons (Price et al 1979, Light & Kavookjian 1988). Ionto­ phoretic application of 5HT (Griersmith & Duggan 1980, Headley et al 1978) into lamina II, where interneurons are concentrated, but not into the deeper laminae, which contain the somata of projection neurons, inhibits the responses of the more deeply situated units to noxious stimu­ lation. Further studies are needed to determine whether this inhibition depends upon lamina II interneurons.

Inhibition of an Excitatory Interneuron There is evidence that the dorsal horn contains excitatory interneurons that relay input from primary afferent nociceptors to projection neurons. Since few nociceptive spinothalamic cells located in lamina V have den­ dritic extensions into laminae I and II (Ritz & Greenspan 1985, Carlton et al 1989), where the majority of nociceptive primary afferents, par­ ticularly C-fibers, terminate (Light & Perl 1979a,b, Sugiura et aI 1986), it is likely that nociceptor activation of these deep spinothalamic cells is largely indirect, relayed by cells in lamina II. Recently, Light & Kavookjian ( 1988) described a population of nociceptive lamina II cells that make asymmetric, presumably excitatory, synapses onto dorsal horn neurons in deeper laminae. These lamina II cells could be an excitatory relay for nociceptor input to lamina V. There is also evidence that lamina II inter­ neurons provide an excitatory relay to lamina I projection neurons (Bennett et a1 1979, Price et aI 1979). Consistent with the idea that off-cells inhibit nociceptive transmission in part through inhibition of excitatory interneurons in lamina II of the dorsal horn is the observation that RVM stimulation produces an IPSP in the putative excitatory lamina II inter­ neurons studied by Light & Kavookjian ( 1988).

Excitation of an Inhibitory Interneuron Evidence also indicates that RVM cells excite inhibitory interneurons that in turn inhibit the activity of projection neurons (Figure 2D). As discussed above, there is a population of cells in the superficial dorsal horn that is excited by electrical stimulation of the PAG and by iontophoresis of NE (Millar & Williams 1989). These neurons have low-amplitude extracellular

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spikes, which suggests that they are small, and they are in the appropriate location to serve as the inhibitory interneurons that are excited by 5HT and by RVM off-cells. Immunocytochemical studies also support the notion that descending control is executed partially via inhibitory interneurons. Thus, the super­ ficial laminae of the dorsal horn contain large numbers ofGABA-immuno­ reactive neurons (Magoul et al 1987, Ruda et al 1986, Basbaum et al 1986b, Todd & McKenzie 1989). There are also dense concentrations of immunoreactive enkephalin-containing interneurons and terminals in dorsal horn laminae I and II (Glazer & Basbaum 1981, Ruda et aI1986). Some of the enkephalin-containing neurons in superficial dorsal horn are directly contacted by serotonin-containing terminals, possibly derived from RVM off-cells (Miletic et al 1984, Glazer & Basbaum 1984), and there is a population of cells in the superficial dorsal horn that is excited by iontophoretically-applied 5HT (Todd & Millar 1983). Thus, the exci­ tation of inhibitory opioid interneurons in the dorsal horn could be pro­ duced through a serotonergic synapse presumably derived from an off­ cell. Some of these enkephalin-immunoreactive terminals synapse onto both lamina I and lamina V thalamic relay cells in the dorsal horn (Ruda et al 1984, Priestley & Cuello 1989). Pharmacological studies indicate that spinal opioids, such as enkephalin, play a role in inhibiting nociceptive transmission. That dorsal horn opioid interneurons are a target of off-cell terminals is supported by the obser­ vation that intrathecally administered naloxone blocks the antinociceptive action of RVM stimulation (Zorman et al 1982; cf Aimone et al 1987). Intrathecal administration of enkephalin suppresses nociceptive reflexes, and iontophoretically applied enkephalin inhibits spinothalamic tract neuron responses to noxious pinch and iontophoretically applied glu­ tamate (Willcockson et a1 1986, Yaksh 1981). In vitro studies have demon­ strated an opiate-induced, K + channel-mediated hyperpolarization of some neurons in dorsal horn (Duggan & North 1984, Yoshimura & North 1983). That enkephalin-containing terminals in the dorsal horn inhibit nociception is indicated by the observation that intrathecal administration of enkephalinase inhibitors inhibits nociceptive dorsal horn cells (Dicken­ son et al 1987). SUMMARY

Significant advances have been made in our understanding of nociceptive modulation from RVM. Among the most useful conceptually has been the discovery that there are two classes of modulatory neurons in the RVM

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that are likely to have opposing actions on nociception: on-cells, which may facilitate nociceptive transmission, and off-cells, which probably have a net inhibitory effect on nociception. The similarity in response properties among the members of each class, their large, somatic "receptive fields," and the wide distribution of the terminal fields of axons of individual neurons to the trigeminal sensory complex and to multiple spinal segments indicate that these neurons exert a global influence over nociceptive responsiveness. Drug microinjections into the RVM presumably shift the balance between states of on- or off-cell firing and also produce measurable changes in the threshold for nocifensor reflexes. The meaningful unit of function in the RVM nociceptive modulatory system therefore probably consists of large ensembles of physiologically and pharmacologically similar neurons. The strong coordination of activity of the two classes of RVM neuron may depend largely upon intranuclear projections from RVM off-cells that excite other off-cells and inhibit on-cells. The off-cell pause is GABA-mediated, and it is likely that there is a subset of GABA-containing RVM on-cells that directly inhibit off-cells. Furthermore, the available evidence indicates that exogenous opiates acti­ vate off-cells by inhibiting GABAergic release. Presumably, enke­ phalincrgic cells in the RVM disinhibit off-cells in a similar way. Although non-serotonin-containing off-cells certainly exist, we propose that some off-cells contain serotonin. Other possible connections are based on more limited data; however, ACh, neurotensin, NE, and EAAs are present in neurons that project to the RVM, and each of these compounds, when microinjected into the RVM, has a modulating effect on nociceptive trans­ mission. The local circuits in the RVM that underlie these actions remain to be elucidated. At the level of the dorsal horn, there is good evidence for each of three inhibitory mechanisms: direct inhibition of nociceptive projection neurons, inhibition of excitatory relay interneurons, and excitation of an inhibitory interneuron. The relative contribution made by each of these circuits is unknown. In contrast to the extensive body of information that we have concerning the dorsal horn mechanisms underlying inhibition, we have no information about how the RVM facilitates nociceptive transmission at the level of the dorsal horn, because the research to date on nociceptive modulation has been carried out within a conceptual framework in which the modulatory outflow from the RVM has only inhibitory effects on nociceptive trans­ mission. Future studies must address the issue of the pharmacology and dorsal horn circuitry underlying the facilitation of nociccption.

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ACKNOWLEDGMENTS

Our work has been supported by Public Health Service grants NS 21445 and DA1949, the Bristol-Meyers Squibb Foundation, and the University of California Board of Regents. We thank Allan Basbaum for critical comments and Lael Carlson for editorial support.

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Neurotransmitters in nociceptive modulatory circuits.

Significant advances have been made in our understanding of nociceptive modulation from RVM. Among the most useful conceptually has been the discovery...
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