Neural

mechanisms Donald

University Hyperalgesia, associated hyperalgesia central

or

enhanced

appears

pain-signalling

are not well

sensitivity

Minnesota,

pain,

is

diseases.

by sensitization

Introduction

to our

and sensitization

in Neurobiology

often

Although

of peripheral

mechanisms

contributions

hyperalgesia

USA

a symptom

and various

underlying

Recent

Opinion

to

nerve injury

neurons,

underlying

Current

Minneapolis,

to be mediated

understood.

mechanisms

A. Simone

of Minnesota,

with inflammation,

of hyperalgesia

and

of sensitization knowledge

of the

are reviewed.

1992, 2:479-483

Peripheral

neural

mechanisms

of pain and

hyperalgesia

Under normal conditions, adequate stimuli for evoking a sensation of pain are those that are intense, potentially damaging, and which lead to activation of nociceptors and associated central neurons (for a review, see [l]). Under certain pathological conditions, however, pain can be triggered by stimuli normally perceived as innocuous. This altered sensory state of increased sensitivity to pain is termed hyperalgesia, and is characterized by a lowered pain threshold, increased pain to normally painful stimuli, and often, spontaneous pain. It can occur within injured tissue (primary hyperalgesia) and also in surrounding uninjured tissue (secondary hyperalgesia). The neurophysiological correlate of hyperalgesia is sensitization of peripheral nociceptors or central pain-encoding neurons, and is characterized by a decrease in response threshold, enhanced responses to suprathreshold stimuli, and often, spontaneous activity. There are many different circumstances that can lead to hyperalgesia, including inflammation, tissue injury and a variety of diseases. Therefore, it is not surprising that the underlying mechanisms leading to peripheral or central neuronal sensitization and hyperalgesia are heterogeneous and complex. A great deal of pain research has recently focused on hyperalgesia for several reasons. First, hyperalgesia can be so severe that gentle pressure or light touch evokes a painful sensation. Second, hyperalgesia can be chronic, sometimes lasting for years. Third, hyperalgesia is often difficult to manage clinically. The reason for this is that the underlying pathophysiological mechanisms are not known. In recent years, however, significant contributions have been made with regard to the neural mechanisms that contribute to hyperalgesia. These include investigations into different types of nociceptors and the biochemical mechanisms by which nociceptors become sensitized, the role of peripheral neuropeptides in hyperalgesia, the contribution of peripheral and central mechanisms in secondary hyperalgesia, and the mechanisms underlying sensitization or hyperexcitability of central neurons. This review will discuss recent studies of these issues.

Primary

afferent

nociceptors

The most commonly studied nociceptors are those excited by mechanical, thermal and chemical stimuli (e.g: polymodal). It appears, however, that nociceptors sensitive primarily to noxious chemical stimuli also exist. These chemical nociceptors, or ‘chemonociceptors’, which are normally silent and unresponsive to mechanical and thermal stimuli, may be activated by chemical stimuli and/or develop responsiveness to mechanical or thermal stimuli following chemical stimulation or during inflammation [ 2-51. In the rat sural nerve, it has been shown that nearly 50 % of C-fibers and over 20 % of A&fibers are unresponsive to noxious mechamcal or thermal stimuli [6**]. When noxious stimuli are applied repeatedly, which often produces oedema, a proportion of previously unresponsive units develop sensitivity to mechanical and/or thermal stimuli. Meyer and Campbell [7] have used an electrical search technique to locate receptive fields of mechanically insensitive cutaneous alferents in monkeys. They have shown that a portion of these allerents are chemosensitive, and that some become responsive to mechanical stimuli af ter injection of inflammatory mediators into their receptive field [8-l. These newly discovered nociceptors may be involved in mediating pain and hyperalgesia during inflammation and other painful syndromes.

Inflammation

and sensitization

of nociceptors

It is well known that prostaglandins and other inllammatory mediators contribute to hyperalgesia during inflam mation. Although prostaglandins themselves do not produce pain, they produce hyperalgesia [3-131 and sensitization of nociceptors to both mechanical stimulation and algesic substances such as bradykinin [ 141. Close arterial injection of prostaglandin I, (PG12) and the PGI, analogue, cicaprost, in rats causes activation and sensitization

Abbreviations APED-2-amino-5-phosphonovalerate;

NMDA-N-methylbaspartate;

@

Current

Biology

PCL-prostaglandin

Ltd ISSN 0959-4388

I,; STT-spinothalamic

tract

479

480

Sensory

systems

of articular mechanonociceptors, while prostaglandin Ez exhibits only weak effects in exciting nociceptors [15*]. It has been concluded that PGI, is the major prostanoid mediator for inducing resting discharge and sensitization of articular nociceptors. Further, there is evidence that sensitization of nociceptors and hyperalgesia produced by inflammatory mediators involves the CAMP second messenger system [ 161, Taiwo and Levine [17-l reported that in rats, intradermal injection of forskolin, which activates adenylyl cyclase, lowers the threshold for the flexion reflex evoked by mechanical stimulation. The duration of this hyperalgesic response is prolonged by phosphodiesterase inhibitors, Furthermore, hyperalgesia induced by forskolin or by prostaglandins is antagonized by inhibitors of CAMP, but not protein kinase C. These results demonstrate that CAMP plays a key role in the sensitization of nociceptors during inflammation.

Hyperalgesia

and neuropeptides

Neuropeptides may also contribute to sensitization of nociceptors. It has been shown that subcutaneous injection of neurokinin A, substance P and calcitonin gene-related peptide into the rat paw, lowers paw withdrawal latencies to noxious mechanical stimulation [ 18*]. Dose-response studies have revealed that neurokinin A and substance P are most effective. Additional studies are needed to determine the mechanism by which these peptides produce hyperalgesia, and whether they can have a direct effect on the excitability of nociceptors.

There is also evidence for an interaction between pain associated with the sympathetic nervous system and cytokines [22*], Intraplantar injection of interleuking in rats produces decreased withdrawal latencies to pressure applied to the paw, and this is attenuated by P-adrenergic receptor antagonists and by guanethidine. Much more research is needed to determine the interactions between cytokines, the excitability of nociceptors, the sympathetic nervous system, and pain.

Spinal neural

Neuropathic

pain

of pain and

hyperalgesia It has now been established that, in addition to sensitization of nociceptors, tissue injury and inflammation also result in hyperexcitability (i.e. sensitization) of neurons located in the dorsal horn of the spinal cord. It is believed that sensitization of spinal neurons, characterized by increases in receptive field areas and in responses to peripheral stimulation [ 23-261, mediates hyperalgesia. Al though sensitization of nociceptors may contribute to enhanced responses of central cells, a role for central mechanisms has also been proposed [27.28]. Recent studies of the biochemical and physiological changes that occur in spinal cord neurons during pain and hyperalgesia are described below.

Secondary

The mechanisms by which chronic pain (e.g: causalgia) develops after peripheral nerve injury are unknown, al though the sympathetic nenous system has been implicated. Partial nerve injury in rats, caused by unilateral ligation of about half of the sciatic nerve, produces sensory disorders characterized by abnormally enhanced withdrawal responses to innocuous and noxious stimulation of the partially dealferented skin [ 191. Such behaviors are suggestive of hyperalgesia. These sensory disorders are abolished or diminished by chemical sympathectomy using guanethidine [20*]. Thus, this type of injury provides a model for studying ‘sympathetic maintained pain’. Sato and Per1 [al**] produced a partial injury to the great auricular nerve in rabbits and then exam ined electrophysiological responses of single cutaneous C-fiber polymodal nociceptors within the injured nerve to sympathetic stimulation, and to close arterial injection of norepinephrine. They found that after injury, but not before, a portion of C-nociceptors were excited by both sympathetic stimulation and norepinephrine. These responses were blocked by cr2-adrenergic receptor antagonists. This study provides important information regarding the possible underlying pathophysiology of sympathetic maintained pain. Recordings from C-nociceptors in human patients with neuropathic pain are needed to determine whether similar mechanisms account for certain types of neuropathic pain syndromes.

mechanisms

hyperalgesia

Although primary hyperalgesia is believed to result from sensitization of nociceptors, the neural mechanisms underlying secondary hyperalgesia are less well understood, and both peripheral and central mechanisms have been proposed. Lewis [ 291 was the first to perform quantitative detailed studies of secondary hyperalgesia and postulated that the spread of hyperalgesia away from an injury was mediated by peripheral neural mechanisms. In later studies, Hardy and co-workers [30] proposed that secondary hyperalgesia was mediated by central mechanisms, probably located in the spinal cord. In psychophysical studies of cutaneous secondary hyperalgesia produced by a heat injury, hyperalgesia to both heat and mechanical stimuli occurred within the injured area, while only mechanical hyperalgesia developed in skin surrounding the injury [31]. This suggests that primary and secondary hyperalgesia are mediated by separate mechanisms. Furthermore, it has been demonstrated that mechanical hyperalgesia is mediated by large myelinated alferents, which normally evoke a sensation of touch [32], suggesting central mechanisms. IaMotte and colleagues [33] studied secondary hyperalgesia produced by intradermal injection of 100 ug capsaicin. When injected into human skin, capsaicin evoked burning pain, hyperalgesia to heat in a small area surrounding the injection [33], and a large surrounding area of mechanical hyperalgesia (secondary hyperalgesia) [ 341. A recent series of psychophysical experiments have concluded that secondary hyperalgesia after caps&in injection is neurogenic, in that it is due to neural activity and

Neural

not to diffusion of capsaicin or endogenous algesic substances, and the neurons responsible for mediating secondary hyperalgesia reside in the central nervous system [35**]. This has been confirmed by electrophysiological studies of primary aiferent nociceptors and dorsal horn neurons in anesthetized monkeys. Injection of capsaicin either inside or outside the receptive fields of A- and C-fiber nociceptors failed to enhance their responses to mechanical stimuli [36=*]. Interestingly, recordings were made from afferents of chemical nociceptors excited by the capsaicin injection. Although the role of these allerents in pain sensation is not known, it has been hypothesized that they contribute to sensitization of spinal neurons [35**]. Separate studies have found that spinothalamic tract (SIT) neurons are not only excited by capsaicin injected into their receptive field, but also have enhanced responses to mechanical and heat stimuli [37**]. In addition, the spatial relation between sensitization to mechanical and heat stimuli matched the spatial relation between mechanical and heat hyperalgesia observed in humans - enhanced responses to mechanical stimuli occurred within a large area of the receptive field, while the increased responses to heat were restricted to a small area around the capsaicin injection site. Furthermore, responses of SIT neurons evoked by electrical stimulation of a cut dorsal rootlet were enhanced after capsaicin injection. Collectively, these data demonstrate that SIT neurons contribute to the pain and hyperalgesia produced by capsaicin, and support the notion that secondary hyperalgesia results, at least in part, from central hyperexcitability. Recent studies of the mechanisms by which spinal neurons become hyperexcitable are described below.

Hyperexcitability

of dorsal

horn neurons

It has been proposed that proto-oncogenes, such as c-f&-, can regulate the expression of specific target genes that induce long-term alterations in cell function [38,39]. Nociceptive stimulation and inflammation have been shown to increase neuronal expression of Fos-related proteins in the spinal cord dorsal horn [40]. Preprodynorphin mRNA, which codes for the biosynthesis of the opioid peptide dynorphin, also increases in the spinal cord during inflammation [41,42] and following nerve injury [43*]. Moreover, dynorphin mRNA and Fos-related pro teins are colocalized in rat dorsal horn neurons following peripheral inflammation [440*]. This suggests that one possible function of Fos-related proteins might be to regulate dynorphin gene expression in the spinal cord. One role of spinal dynorphin during inflammation may be to modulate the excitability of dorsal horn neurons [45**]. Approximately one-third of rat dorsal horn neurons exhibit expansion of their receptive fields after application of dynorphin or another x-opioid receptor agonist (U-50, 488H) to the spinal cord. In addition, low doses of U-50, 488H facilitate responses to mechanical and heat stimuli. These results suggest that dynorphin may contribute to hyperalgesia during inflammation by enhancing the excitability of spinal neurons.

mechanisms

of hyperalgesia

Simone

There is evidence from behavioral studies that neurokinins, such as substance P, and excitatory amino acids may also contribute to hyperalgesia, as intrathecal administration of these substances [ 46,471 induces nociceptive behavior. Intrathecal administration of an N-methyl-D-aspartate (NMDA) receptor antagonist or a neurokinin receptor antagonist decreases nociceptive behavior in a model of tonic pain (subcutaneous injection of formalin) [48-l. These results suggest that both excitatory amino acids and neurokinins are involved in the spinal processing of prolonged pain and hyperalgesia, such as that associated with inllammation. In addition, there is evidence that excitatory amino acids enhance the excitability of dorsal horn neurons. Dougherty and Willis [49**] have shown that responses of primate spinothalamic tract neurons, evoked by innocuous mechanical stimulation of the skin, are enhanced by microiontophoretic application of t-glutamate and NMDA. Schaible et al [50**] have demonstrated that the NMDA antagonists ketamine and D-2-amino-5-phosphonovalerate (AP5) reduce the hyperexcitability (spontaneous activity and responses to mechanical stimulation) of cat spinal neurons evoked by acute arthritis in the knee joint. These studies provide important insight into the spinal mechanisms and possible pathophysiology underlying pain and mechanical hyperalgesia associated with inflammation and other chronic painful syndromes.

Conclusion A wide variety of approaches, from behavioral to molecular biological, are being used to increase our understanding of the neural mechanisms underlying the sensation of pain and hyperalgesia. In particular, significant advances are being made in our understanding of how excitability of peripheral and central pain-signalling neurons can change, and thereby result in abnormal painful sensations by normally innocuous stimuli. It is clear that tissue injury and inflammation not only produce sensitization of peripheral nociceptors, but also enhance the excitability of spinal neurons. It is this increased excitability that most likely contributes to hyperalgesia. Continued research using a variety of behavioral models and experimental techniques will provide an understanding of the circumstances leading to chronic painful syndromes and the underlying pathophysiology.

References

and recommended

hpers of particular interest, published view, have been highlighted as: of special interest . of outstanding interest .. 1. 2.

reading

within the annual period of rep

BAJA SN, MEYER RA, C.~PBELL JN: Peripheral Mechanisms Somatic Pain. Anesthesiology 1988, 68:571-590. LtMom

of

RH, SIMONE DA, BAUMANNTK, SHAIN CN, ALFEJAM:

Hypothesis Chemogenic

for Novel Classes of Chemoreceptors Mediating Pain and Itch. In Pain Research and Clirzical

481

482

Sensory

systems

Management. Edited by Dubner R, Gebhart Amsterdam: Elsevier; 1988, II: 529-535.

GF, Bond

MR.

the most potent and the cakitonin gene-related peptide the least. A role for peripheral neuropeptides in hyperalgesia is demonstrated. SELTZERZ, DLJRNERR, SHIR Y: A Novel Behavioral of Neuropathic Pain Disorders Produced by Partial Nerve Injury in Rats. Pain 1990, 43:205-218.

3.

SCHAIBLE HG, SCHMIDT RF: Excitation and Sensitization of Fine Articular ARerents from Cat’s Knee Joint by Prostaglandin E2. J Pbysiol 1988, 404:91-105.

19.

4.

SCHALBLEHG, SCHMIDT RF: Time Course of Mechanosensitivity Changes in Articular Afferents During a Developing Experimental Arthritis. J Neuropbysiol 1988, 60:2180-2196.

5.

HASIER HJ, JANIC W, KOL’IZENBURGM: Activation

SHIR Y, SELTZER2: Effects of Sympathectomy in a Model of Causalgiform Pain Produced by Partial Sciatic Nerve Injury in Rats. Pain 1991, 45:309-320. Chemical sympathectomy with guanethidine alleviated nociceptive behavior following sciatic nerve injury in rats. This provides a potential animal model of ‘sympathetic maintained pain’.

Iinated AITerent Fibres mation of the Urinary 425:545-562.

20. .

of Unmyeby Mechanical Stimuli and InfIamBladder of the Cat. ,I Pbysiol 1990,

6. ..

HANDWRKER HO, KIIX) S, REEH PW: Unresponsive

7.

MEXR RA, CAMPBELLJN: A Novel Electrophysiological Technique for Locating Cutaneous Nociceptive and Chemospecific Receptors. Brain Res 1988, 448-86.

8.

MEYER RA, DAVIS KD,

AfTerent Nerve Fibres in the SuraI Nerve of the Rat. J Pbysiol 1991, 435229242. A large proportion of the Cmand A-fiber cutaneous a&rents in the rat could not be excited by mechanical or thermal stimuli. Some afferents became responsive after repeated stimulation, however.

COHEN RH, TKEEDE R-D, CAMPBELL

..

JN: Mechanically Insensitive merents (MIAs) in Cutaneous Nerves of Monkey. Brain Res 1991, 561:252-261. Cutaneous tierents that did not respond to mechanical stimulation, but that were excited by intradennal injection of inflammatory median tars into the receptive field, were found in monkey. A portion became sensitized to mechanical stimulation. Further research is needed to Deb termine the role of these chemical receptors in pain and hyperaigesia associated with inflammation. 9. 10. 11.

CRLJNKHOFLNP, WILLISAL: Cutaneous

Prostaglandins.

Br J j’barmacol

COILIER HOJ,

SCHNEIDER C:

Prostaglandins.

Nature

FERRERWSH: Prostaglandins,

sia. Nuture

JUAN H: Prostaglandins cd 1978, 9:403-409.

13.

FERREIIRA SH: Peripheral

14.

Aspirin-Like

Responses

16.

CUNHA FQ, IORENZTTI BB, POOLE S, FERREIRASH: Interleukin-

23.

C~K AJ, WOOLF CJ, WALL PD, MCMAHON SB: Dynamic Receptive Field Plasticity in Rat Spinal Cord Dorsal Horn Following C-Primary Afferent Input. Nature 1987, 325:151-153.

24.

HYLDENJLK, NAHIN RL, TRAUBRJ, DUBNERR: Expansion of Receptive Fields of Spinal Lamina I Projection Neurons in Rats with Unilateral Adjuvant-Induced Inflammation; the Contribution of Dorsal Horn Mechanisms. Pain 1989, 37:223-243.

25.

HOHEISEI.U, MENSE S: Long-Term

26.

WOOLF CJ, KING Al?: Dynamic Alterations in the Cutaneous Mechanoreceptive Fields of Dorsal Horn Neurons in the Rat Spinal Cord. J Neurosci 1990, 10:2717-2726.

27.

WOOLF CJ: Evidence for a Central Component of Post-Injury Pain Hypersensitivity. Nature 1983, 306686688.

2x.

NEIJ~EBAIJERV, SCHAIBLEH-G: Evidence for a Central Component in the Sensitization of Spinal Neurons with Joint Input During Development of Acute Arthritis in Cat’s Knee. J Neuropbysiol 1990, 64:29!+311.

29.

LEWIST: Experiments Relating to Cutaneous HyperaIgesia and its Spread Through Somatic Nerves. Clin Sci 1936, 2373-421.

30.

~IARDY JD, WOOIP HG, GOODEIL 1-I: Experimental

8 as a Mediator of Sympathetic Pain. Br J Pharmacol 1991, 104~765-767. Intraplantar injection of interleukin-8 produced a dose~dependent hyperalgesia in rats which was attenuated by guanethidine.

Drugs and Analge-

as Modulators and Central

of Pain. Gen !%urmaAnalgesia. In AdzJaances

and Re.search and 7hrapy Edited by Bonica JJ, LJ, Iggo A. New York: Raven Press; 1983, V: 627-634.

MEN% S, Sensitization of Group Bradykinin by 5.Hydroxytryptamine Brain Re.s 1981, 255:95-105.

IV Muscle Receptors and Prostaglandin

to E2.

BIRREIL GJ, MCQUEEN DS, Iwo

TAIWOYO, BJERKNESL, GOETZI. EJ, LEVINEJD: Mediation of primary AlTerem Hyperalgesia by the CAMP Second Messenger System. Neuroscience 1989, 32:577-580.

17. .

TAIWO YO, LEL?NIZJD: Further Confirmation of the Role of Adenyl Cyclase and of CAMP-Dependent Protein tinase in Primary Afferent Hyperalgesia. Neuroscience 1991, 44:131-135. Intradermal injection of forskolin, which activates adenylyl cyclase, Lowe ered nociceptive threshold to mechanical stimulation. Hyperalgesia produced by forskolin or prostaglandins was not attenuated by inhibition of protein kinase C. 18. .

22. .

to

A, COIEMANRA, GIXIBB BD: PG12-Induced Activation and Sensitization of Articular Mechanonociceptors. Neurosci Lett 1991, 124:5-s. Inrrddermal injection of PG12 or cicaprost caused excitation and sensitization of joint mechanonociceptors. The authors demonstrate the importance of PGI, receptors in mediating prostagkindin hyperdgesid.

15 .

Excitation of Cutaneous Pain SATO J, PERL ER: Adrenergic Receptors Induced by Peripheral Nerve Injury. Science 1991, 251:160%1611. Following partial peripheral nerve injuly in rabbits, C-fiber polymodal nociceptors became responsive to smpathetic stimulation and to norepinephrine. Responses to sympathetic stimulation and norepinephrine were blocked by a*-adrenergic receptor antagonists. 21. ..

1972, 240:200-203.

12.

in Pain tindblom

Reactions to IntradermaI 1971, 41:4%56.

Nociceptive 1972, 236:141&143.

Model Sciatic

NAKAMUR.&RAIGM, GILL BK: Effect of Neurokinin A, Substance P and Caicitonin Gene Related Peptide in Peripheral HyperaIgesia in the Rat Paw. Neurosci Lett 1991, 124:4’+51. Subplantar injections of neurokinin 4 substance P and calcitonin generelated peptide in rat5 produced hyperalgesia, with neurokinin A being

Changes in Discharge Behavior of Cat Dorsal Horn Neurones Following Noxious Stimulation of Deep Tissues. Pain 1989, 36:23‘+247.

on the Nature 29:115-140.

of Cutaneous

Hypcralgesia.

Evidence .I Clin Inzjest 1950,

31.

BAJA SN, C.wffwf.f.JN, MEVER RA: Evidence for Different Mechanisms of Primary and Secondary Hyperalgesia Following Heat Injury to the Glabrous Skin. Brairz 1984, 107:117~1188

32.

MEWR RA, CAMPBELLJN: MyeIinated AtTerents Account for the Hyperalgesia that Follows a Bum to the Hand. Scbnce 1981, 213:1527-1529.

33.

SIMONEDA, NGEOW JYF, PUT~ERMANGJ, IAMOTTE RH: Hyperalgesia to Heat after Intradermal Injection of Capsaicin. Bruin Res 1987, 418:201-203.

34.

SIMONEDA, BAUMANNTK, L&lo’rr~

RH: Dose-Dependent Pain and Mechanical Hyperalgesia in Humans after Intradermal Injection of Capsaicin. Pain 1989, 38:99-107.

35. ..

LAMOTTE RH, SHAIN CN, SIMONE DA, TSAI EFP: Neurogenic

Hyperalgesia: Psychophysical Studies of Underlying Mechanisms. J Neurophysiol 1991, 66:190-211. IntradermaJ injection of capsaicin in humans produced a neurogenic hyperalgesia that was characterized by a secondary hyperalgesia to

Neural

Innocuous mechanical stimuli. Experiments with nerve blocks suggest that the neurons responsible for mechanical hyperalgesia are in the central nervous system. BAUMANN TK, SIMONEDA, SHAIN CN, L%Mom RH: Neurogenie Hyperalgesia: the Search for the Primary Cutaneous Afferent Fibers that Contribute to Capsaicin-Induced Pain and Hyperalgesia. J Neurop&iol 1991, 64:212-226. Intradermal injection of capsaicin either inside or outside the receptive fields of A- and C-fiber nociceptors in monkeys did not enhance responses to mechanical stimulation. It was also found that capsaicin activated chemical nociceptors unresponsive to mechanical and thermal stimuli.

36. ..

37. ..

SIMONE DA, SORKINLS, OH U, CHLJNG JM, OWENS C, LAMO’ITE

RH, WILLIS WD: Neurogenic HyperaIgesia: Central Neural Correlates in Responses of Spinothalamic Tract Neurons. J Neurophysiol 1991, 64:228-246. Activation and sensitization of SIT neurons in monkeys by intrader mal injection correlated with psychophysical measures of pain and hyperalgesia in humans. It was also shown that after capsaicin injection, responses of STT neurons to electrical stimulation of a cut dorsal rootlet were enhanced. It is suggested that hyperalgesia after capsaicin injection involves central sensitization. 38.

MORGAN Jl, CURRANT: Stimulus-Transcription Coupling in Neurons: Role of Cellular Immediate-Early Genes. Trend Neurosci 1989, 12:45+462.

39.

SHENG M, GREENHERG ME: The Regulation and Function of C-Fos and Other Immediate Early Genes in the Nervous System. Neuron 1990, 4:477-485.

40.

MENETREY D, GANNON A, LEVINE JD, B~~RALJMAI: Expression of C-Fos Protein in Interneurons and Projection Neurons of the Rat Spinal Cord in Response to Noxious Somatic, Articular, and Visceral Stimulation. J Comp Neural 1989, 285:177-195.

41.

L~DAROLA MJ, BRADYIS, DRA~SCIG, DUBNERR: Enhancement of Dynorphin Gene Expression in Spinal Cord Following Experimental Inllammation: Stimulus Specificity, Behavioral Parameters and Opioid Receptor Binding. Pain 1988, 35:313-326.

42.

RUDAMA, IAD~OLA MJ, COHENLV, YOUNG WS III: In Situ Hybridization Histochemistry and Immunocytochemistry Reveal an Increase in Spinal Dynorphin Biosynthesis in a Rat Model of Peripheral Inflammation and Hyperalgesia. Proc Natl Acad Sci USA 1988, S5:622426.

43. .

DKAISCI G, UJANDERKC, DUBNERR, BENNETTGJ, IADARou MJ:

44. ..

NOGLJCHI K, KOWALSKIK, TRAUB R, SOLODKIN A, IAIXROLAMJ, RUDA MA: Dynorphin Expression and Fos-Like Immunoreactivity Following Inflammation Induced HyperaIgesia are Colocalized in Spinal Cord Neurons. Mol Brain Res 1991, 10:227-233.

Up-Regulation of Opioid Gene Expression in Spinal Cord Evoked by Experimental Nerve Injuries and Intlammation. Brain Res 1991, 560:186192. A chronic constriction injury to the sciatic nerve in rats, and peripheral intlammation evoked by subcutaneous carrageenan, each produced increased levels of preprodynorphin mRNA in the spinal cord. These observations suggest that the dynorphin system is activated during Peru sistent pain states.

mechanisms

of hyperalgesia

Simone

This study demonstrates that during peripheral inflammation, approximately 80 % of spinal neurons exhibiting increased levels of dynorphin mRNA or the peptide also exhibit increased levels of Fos-related proteins. Suggests that activation of Fos and related proteins may be involved in regulating dynorphin gene expression in spinal neurons. HYLDEN JLK, NAHINRL, TRAUBRJ, DUBNERR: Effects of Spinal Kappa-Opioid Receptor Agonists on the Responsiveness of Nociceptive Superticial Dorsal Horn Neurons. Pain 1991, 44:187-193. Application of x-opioid receptor agonists to the rat spinal cord produced an expansion of receptive fields and increased responses to mechanical and/or thermal stimuli. These data suggest that one function of the increased levels of spinal dynorphin during inflammation may be to contribute to enhanced excitability of dorsal horn neurons. 45. ..

46.

MATSUMURA H, SAKURADA T, HARAA, SAK~JRADA S, KISARAK: Characterization of the Hyperalgesia Effect Induced by Intrathecal Injection of Substance P. Neuropharmacology 1985, 24:421426.

47.

AANONSEN LM, WILCOXGL: Nociceptive Action of Excitatory Amino Acids in the Mouse: Effects of SpinaIly Administered Opioids. J Pharmacol Exp ?her 1987, 243:9-19.

M~JRRAYCW, COWAN A, LARSONAA: Neurokinin and NMDA Antagonists (but not a Kainic Acid Antagonist) are Antinociceptive in the Mouse Formalin Model. Pain 1991, 44:179-185. Nociceptive behavior produced by subcutaneous injection of formalin in mice is decreased by neurokinin and NMDA receptor antagonists. These data support the notion that neurokinin and NMDA receptors are involved in the spinal processing of tonic nociception. 48. .

DOUGHERT/PM, WILLISWD: Modification

of the Responses of Primate Spinothalamic Neurons to Mechanical Stimulation by Excitatory Amino Acids and an N-Methyl-D-Aspartate Antagonist. Bruin Res 1991, 542:1>22. Using combined microiontophoresis and electrophysiological techniques, responses of primate SIT neurons to innocuous mechanical stimulation are shown to be facilitated by glutamate and NMDA (and quisqualate for some cells). These results suggest that excitatory amino acids contribute to the hyperexcitability of spinal neurons and to hyperalgesia. 49. ..

SCHAIBLEH-G, GRUBB BD, NEIJGERAUERV, OPPMANNM: The Effects of NMDA Antagonists on Neuronal Activity in Cat Spinal Cord Evoked by Acute Inflammation in the Knee Joint. Eur J Neurosci 1991, 3:981-991. In this study, the effects of NMDA antagonists on discharges of cat spinal neurons, rendered hyperexcitable by acute arthritis of the knee joint, were examined. Intravenous administration of ketamine, and ions tophoretic application of ketamine or AP5, decreased spontaneous activity and responses evoked by mechanical stimulation of the inflamed joint. These results further demonstrate a role for NMDA receptors in the hyperexcitability of spinal neurons. 50. ..

DA Simone, DqJdrtIIIetIt of Psychiatry, Division of Neuroscience Research, University of Minnesota, 420 Delaware Street S.E., Box 392 UMHC, Minneapolis, Minnesota 55455, USA.

483