Novel Pharmacological Strategies for Analgesia

Annals ofthe Rheumatic Diseases 1996;55:715-722 715

REVIEW: PAIN Series editor: Bruce L Kidd Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from

Novel pharmacological strategies for analgesia

Martin Perkins, Andy Dray

Acute transient pain, associated with negligible The two most studied of these are bradykinin tissue damage, serves as a physiological and kallidin, a nonapeptide and a decapeptide warning of potential tissue damage. Somewhat respectively. Both are cleaved from precursor more persistent pain, associated with molecules following the activation of a hyperalgesia and tenderness, is often associated biochemical cascade. In the plasma, bradykinin with inflammation. This is also a normal (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is protective response to mild injury and resolves produced from high molecular weight rapidly once the injury has healed. However kininogen (HMWK) whereas in tissue kallidin there are various persistent pain conditions in (lysyl-bradykinin) is liberated from its which the stimulus and pain are unrelated. precursor, low molecular weight kininogen Thus the pain sensation outlasts its biological (LMWK)4 by the action ofproteolytic enzymes usefulness. In these conditions pain can no (fig 1). longer be regarded as a purely physiologically Both bradykinin and kallidin are rapidly protective symptom. This may arise as a result degraded by peptidases known as kininases of chronic pathological lesions or degenerative giving rise to inactive metabolites with the processes, but in many cases there may be no exception of des-Arg9bradykinin or des- discernible pathology. These types of chronic Arg'0kallidin which lack the carboxy- terminal pain state-which occur with migraine, arginine. These are the only metabolites of rheumatoid arthritis, osteoarthritis, low back bradykinin or kallidin with significant activity.4 pain, cancer pain, and neuropathic pain-are Bradykinin and kallidin mediate their effects poorly understood and for the most part diffi- through two main classes of receptor, B1 and cult to treat. Thus chronic pain sufferers of one B2.' The genes for both of these receptors have kind or another account for approximately 10- recently been cloned and have been shown to 20% ofthe adult population, while about 5-8% belong to the superfamily of receptors of G

experience pain which is inadequately treated.' protein coupled, 7-transmembrane spanning http://ard.bmj.com/ Present treatment for most pain states has domains receptors.6 7 Less is known about the relied heavily on the use of non-steroidal anti- molecular characteristics ofthe B1 receptor but inflammatory drugs (NSAID) and opioid anal- it has little homogeneity with the B2 receptor8 gesics. Although variants of these classes of and in keeping with current pharmacological drug have been developed there has been little studies it seems likely that antagonists for this conceptual innovation in analgesia for many receptor will be different from those developed

years. Furthermore both classes of drug at B2 sites. on October 1, 2021 by guest. Protected copyright. produce side effects, such as gastrointestinal Bradykinin and kallidin acts preferentially disturbances, gastric ulceration, renal damage, on the B2 receptor, and this accounts for the and hypersensitivity reactions with NSAID, majority of the acute pharmacological effects and nausea, constipation, confusion, respira- of bradykinin. The preferred agonists for the tory depression, and possibly dependence with B1 receptor, however, are the active metabolites, opioids. Despite considerable effort these des-Arg'bradykinin and desArg'0kallidin. problems have not yet been overcome. An Bradykinin exerts a variety of effects on important reason for this has been the many body tissues but it is its actions on noci- relatively slow advance, until recently, in ceptive neurones that are of most relevance to understanding the pathogenesis of chronic pain and analgesia. Bradykinin has two main pain. Some of these advances have been effects on these neurones-activation and reviewed and are leading a conceptual shift in sensitisation-and both of these actions have pain pathophysiology and management. In the been shown to be mediated primarily by the B, light of this we shall discuss some recent initia- receptor. Sandoz Institute for tives for the discovery and development of new Bradykinin depolarises sensory neurones by Medical Research, analgesic drugs based on knowledge of the activation of phospholipase C and stimulation Gower Place, London and neurochemical changes WC1E 6BN, United pathophysiological of protein kinase C, with an increase in Kingdom that occur in the nociceptive pathway after membrane sodium ion conductance.9 '0 This M Perkins injury. probably underlies the overt pain response to A Dray bradykinin. With respect to sensory neurone Correspondence to: Kinin receptor inhibition activity, bradykinin has been shown to increase Dr M N Perkins. Kinins are a family of small peptides which are nociceptor C fibre discharge in somatic and Accepted for publication produced locally in response to tissue injury or visceral sensory neurones both in vitrol' 1' and 19 February 1996 trauma and particularly during inflammation. in vivo." 716 Perkins, Dray

Following administration to somatic and vis- Recently several studies have showed that ceral tissue sites bradykinin elicits powerful during inflammation there is an increasing nocifensor behaviours.13 '5 Bradykinin is also contribution ofB, receptors to the accompany- Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from algogenic in man following topical application ing hyperalgesia. Thus B1 receptor antagonists or intracutaneous injection.16 17 Bradykinin also such as Leu8,des-Arg9bradykinin are consist- has a powerful sensitising action on nociceptors, ently antinociceptive.23 26 27 28 enhancing their responsiveness to mechanical The B, receptor appears to be expressed or and thermal stimulation.'8"20 This property of synthesised de novo in tissues following trauma bradykinin is possibly of more relevance in or when inflammatory mediators such as man, increasing both the perception and dura- cytokines are present.2329 Indeed a close tion of pain. interaction has been shown between kinins other Although bradykinin is one of the first inflammatory mediators, particularly cytokines. inflammatory mediators to be produced in In particular, interleukin-1[ upregulates B, and response to trauma or inflammation, prostaglan- B2 receptors as well as enhances responses to dins also play a major role in inflammation and bradykinin and desArg' bradykinin.23 27 3032 The enhance bradykinin induced responses. Not potential exists, therefore, for a powerful only is the neuronal activation by bradykinin reinforcement between kinins and other potentiated by prostaglandins but they may inflammatory mediators leading to a sustained also enhance bradykinin evoked release of the hyperalgesic state. neurogenic inflammatory mediators substance P and calcitonin gene related peptide Cyclo-oxygenase inhibition (CGRP).2 One of the major treatments for inflammatory There are therefore strong experimental pain has been the reduction of prostaglandin grounds for targeting the B2 receptor in the levels by inhibition of cyclo-oxygenase (COX) treatment of inflammatory pain and conse- activity with NSAID. However, the develop- quently selective B2 receptor antagonists based ment of tolerance and unacceptable side on the peptide structure of bradykinin have effects, such as gastric haemorrhage and neph- been developed (fig 2), the most potent being rotoxicity, have severely limited the usefulness HOE 140.22 The use of this and other of this approach with respect to chronic or per- peptidergic antagonists has shown that the sistent inflammatory pain. It had been thought acute activation and sensitisation of sensory that there was a single cyclo-oxygenase enzyme neurones by bradykinin are mediated by the B responsible for prostaglandin production; receptor.5 23 Furthermore, in several models of however, recently two isoforms of cyclo- nociception, selective B2 receptor antagonists24 25 oxygenase have been demonstrated-a consti- are antinociceptive. tutive and an inducible enzyme (fig 3).3 The BRADYKININ and INFLAMMATORY PAIN http://ard.bmj.com/

Activation of kallikrein enzymes

Precursor molecules high and low molecular weight kininogen on October 1, 2021 by guest. Protected copyright.

PLASMA TISSUE desArg9Bk BRADYKININ Kallidin desArqlOKd ArgProGlyPheSerProPheArg LysArgProProGlyPheSerProPheArg

|RECEPTORS|

Linked with trauma/injury Majority of Bk's actions

Immunocompetent cells - inflammatory SENSORY NERVESA EXCITATION NOCICEPTORS SENSITISATION Figure 1 Theformation of kininsfoUlowing trauma andlor an inflammatory insult. Both bradykinin and kallidin act on the B2 receptor. In addition, kallidin can be converted to bradykinin by the action ofaminopeptidases. The preferred agonistsfor the B1 receptor are desArg9bradykinin (desArg9Bk) and desArgJ°kallidin (desArglOKd) which areformed by the action ofkininase I-peptidase which removes the carboxy-terminal arginine residue ofbradykinin and kallidin, respectively. Bradykinin and kallidin act directly on nociceptive neurones to cause overt excitation, leading to pain, and sensitisation of the terminals resulting in a reduction in thresholdfor activation. In addition, both these kinins act on immunocompetent cells (for example, macrophages) to release other inflammatory mediators such as prostaglandins and cytokines. The B, receptor is expressed on smooth muscle and other tissues such as endothelial cells and is upregulated following inflammation. Novelpharmacological strategies for analgesia 717

Bradykinin receptor ligands|

Agonists I Antagonists Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from B, Des-Arg9 Bradykinin Des-Arg9 Leu8 Bradykinin H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-OH H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Leu-OH B2 Bradykinin HOE 140 (Icatibant) H-Arg-Pro-Pro-GIy-Phe-Ser-Pro-Phe-Arg-OH H-(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Oic-Arg-OH Kallidin NPC567 H-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH H-(D)Arg-Arg-Pro-Hyp-Gly-Phe-Ser-(D)Phe-Phe-Arg-OH NPC1 6731 H-(D)Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(D)Tic-Tic-Arg-OH Figure 2 Structures ofagonists and antagonists for the kinin B, and B2 receptors. constitutive enzyme (COX-1) is present in vir- sensitised nociceptors, possibly through the tually all tissues and is important for the main- nitric oxide-cGMP system.4' Further work is tenance of normal cell function, particularly in needed to establish whether it would be possi- the gastrointestinal tract and kidney. It is inhi- ble to develop NSAID which effectively reverse bition of this isoform that is probably responsi- nociceptor sensitisation without inhibition of ble for the gastric and renal toxicity associated prostaglandin production. with sustained NSAID treatment.' COX-2 is virtually absent in normal tissues but is Nitric oxide synthase inhibition induced following an inflammatory insult such In the last few years there has been great inter- as carrageenin or endotoxin administration.""8 est in the physiology and pharmacology of The underlying trigger for the induction of nitric oxide (NO). This small gaseous molecule COX-2 is still not entirely clear but is generated from L-arginine by nitric oxide interleukin-1 has been shown to induce the synthase (NOS) activity.4' Once generated, NO expression of mRNA for COX-2 as well as acts as an intercellular messenger, diffusing to increasing its activity in many cell types, its target tissue, and stimulates soluble including primary human cell cultures or cell guanylate cyclase, thus increasing cGMP lines."39 40 levels. The increased intracellular concentra- It has been proposed that the inhibition of tion of cGMP then regulates a variety of COX-2 produces an anti-inflammatory and intracellular enzymes including protein kinases

analgesic effect whereas the inhibition of and phosphodiesterases. http://ard.bmj.com/ COX-1 induces the toxic side effects attributed Nitric oxide synthase, like cyclo-oxygenase, to NSAID. All the NSAID in current use has also been shown to exist primarily in two inhibit both enzyme isoforms. However, most forms, a calcium-calmodulin dependent enzyme of them are either more potent inhibitors of which is expressed constitutively in neuronal COX-1 than COX-2, for example, indometh- and other tissues (cNOS) and an inducible acin, ibuprofen and aspirin, or approximately form of the enzyme (iNOS), the activity of

equipotent, for example, diclofenac and aceta- which is calcium independent. In addition, on October 1, 2021 by guest. Protected copyright. minophen,4' and all ofthese are associated with however, there are two isoforms of cNOS, so toxic side effects. Ibuprofen is, however, less far located in endothelial cells and brain.' In ulcerogenic than aspirin and this may be the CNS, iNOS has been primarily located to related to observation that it is more potent at glial cells45 but recently there has been a report inhibiting COX-2 than aspirin.42 Dexametha- showing iNOS in cerebellar neurones.46 The sone also preferentially inhibits inflammation relative roles of constitutive and inducible induced COX-2 activity.37 Recently, much NOS in neurones, remain to be clarified. more selective COX-2 inhibitors have been Nitric oxide synthase has been localised in developed, such as NS398, BF-389, and both somatic and visceral sensory ganglia, par- SC-58125, which have been shown to possess ticularly in small capsaicin sensitive cells with a anti-inflammatory and anti-nociceptive prop- dense concentration of the enzyme in the erties in animal models, with no evidence of superficial laminae of the spinal cord where gastric toxicity."6 37 42 Selective inhibition of nociceptive afferents terminate, supporting a COX-2 may therefore provide a means of alle- central as well as a peripheral role for NO in viating inflammatory pain without the damag- nociception.4748 In addition, following periph- ing side effects associated with present eral nerve lesion there is an increase in immu- treatments. noreactive NOS and mRNA for NOS in dorsal In addition to the development of NSAID root ganglia suggesting that it may play an with COX 2 selectivity there is the possibility important role in the peripheral neuropathy.49 that some ofthe NSAID may have an analgesic Studies to elucidate the functional role of action distinct from inhibition of prostanoid NO have either used inhibitors of nitric oxide synthesis. A recent study has suggested that synthase based on guanidino-monosubstituted diclofenac maybe have an anti-hyperalgesic derivatives of L-arginine, such as L-NG-nitro action through the downregulation of arginine methyl ester (L-NAME) and 718 Perkins, Dray

COX 1 Prostaglandins (PGE2, PGI2)

Constitutive Thromboxanes Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from

AIIZ0QQo:O RequIatory functions eg signal transduction NSAIDS clotting etc Stomach Kidney Platelets eg aspirin, ibuprofen indomethacin

I.- Inflammatory mediators P- COX 11 Prostaglandins eg intereukin-1 P, TNFa Inflammatory mediators Induced 4 At TRAj Immunocompetent cells eg macrophages, leucoctes 270N fibroblasts, epthelial cells COX Il-specific Dexamethason inhibitors eg NS-398, BF-389 SC-581 25 Figure 3 The two isoforms ofcyclo-oxygenase subserve differentfunctions within the body. COX-1 is the constitutive enzyme and is involved in normal, physiological regulatory processes such as signal transduction. COX-2 is induced in immunocompetent cellsfollowing trauma andlor damage and has a role in the generation and maintenance of inflammation. Existing NSAID (eg, aspirin, ibuprofen) inhibit both isoforms of the enzyme but it is their action on COX-1 that is thought to result in renal and gastric toxicity. The induction or activity of COX-2 can be blocked by dexamethasone and, more recently, by specific inhibitors of this enzyme. Such compounds have been developed with the expectation that they will be anti-inflammatory but devoid of the toxic side effects seen with existing cyclooxygenase inhibitors.

L-NG-monomethyl arginine (LNMMA), or root ganglia in rats following a peripheral nerve compounds which increase NO levels such as injury. This suggests a role for NO in the main- L-arginine and sodium nitroprusside.43 Nei- tenance of spontaneous pain following

ther L-NAME nor L-NMMA, however, neuropathic lesions.57 Although there are few http://ard.bmj.com/ discriminate between neuronal and endothelial studies relating to NO and pain in man, a nitric oxide synthase. Recently, a novel recent report showed that NO was algesic inhibitor of nitric oxide synthase, 7-nitro- when injected intracutaneously.5" indazole, has been described which shows Although the bulk ofthe evidence supports a selectivity for the neuronal form of the pro-nociceptive role for NO there are also enzyme.50 This agent has been shown to be reports suggesting an anti-nociceptive action

anti-nociceptive in mice at doses that have no for this mediator. Most of this evidence relates on October 1, 2021 by guest. Protected copyright. effect on blood pressure or vascular smooth to the administration of the precursor for NO, muscle in vitro.0 This raises the possibility that L-arginine. Thus, L-arginine has been shown a nitric oxide synthase inhibitor could be to be anti-nociceptive when given centrally or developed that is anti-nociceptive but devoid of peripherally, possibly through an endogenous cardiovascular side effects. opioid action as its actions were reversed by There are many studies supporting a role for opioid receptor antagonists.54 .. 60 In addition, NO in nociception but the precise involvement L-arginine itself can potentiate opioid induced is not yet clear. NO is pro-nociceptive in analgesia.6' There is also evidence that NO animal models of hyperalgesia. and inhibitors mediates some of the nociceptive actions of of nitric oxide synthase are antinociceptive NMDA within the spinal cord.56 against thermal and chemical stimuli. Thus Part of the confusion may lie with the differ- L-NAME, but not its inactive isomer ent roles that NO may subserve in nociceptive D-NAME, reversed formalin induced foot perception and transmission. NO may well be licking and acetic acid induced writhing in involved as a second messenger mediating mice and carrageenin induced thermal some of the effects of neuronal transmitters hyperalgesia in rats. These effects were both centrally and peripherally, but it may also reversed by the NO precursor L-arginine.5'-55 contribute directly to the generation and main- NO does not, however, appear to be involved in tenance of hyperalgesia. In the former case, the mechanical hyperalgesia as L-NAME has therefore, inhibition of nitric oxide synthase no effect in carrageenin induced hyperalgesia.55 could lead to hyperalgesic or analgesic However NO has also been shown to be responses, depending on whether the neuronal involved in thermal hyperalgesia in neuro- circuits that use NO as a second messenger pathic pain in the rat.56 In addition, L-NAME raise or lower nociceptive thresholds. Where reduced the ongoing discharge seen in dorsal NO is one of the primary hyperalgesic agents Novel pharmacological strategies for analgesia 719

such inhibition would be expected to be The anti-nociceptive properties of capsaicin, antinociceptive, and indeed this is largely the together with its selectivity for polymodal noci- case. ceptors, have made it of particular interest to Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from An additional complication lies in the those studying pain mechanisms and as a pos- specificity of some of the pharmacological sible target for future drug development.' tools used to manipulate NO levels. In particu- Locally applied capsaicin has been used lar, L-arginine, which is used to raise NO con- clinically to alleviate painful conditions such as centrations in many studies, may also be effec- postmastectomy pain, reflex sympathetic tive as a precursor of kyotorphin which is a dystrophy pain, diabetic neuropathy, and post- substance reported to be an endogenous Met- herpetic neuralgia.7""7 However, the usefulness enkephalin releaser.62 Increasing NO levels of capsaicin itselfin these conditions is severely within the CNS by the use of L-arginine may limited by the initial burning sensation experi- therefore also increase the levels of this endog- enced with this compound, which can be severe enous opioid. Such a mechanism may contrib- enough to lead to patients discontinuing the ute to the reported anti-nociceptive actions of treatmnent. It has therefore been challenging to L-arginine, particularly where there is evidence separate the excitatory and pungent actions from for an opioid involvement in this phenom- the antinociceptive properties, and indeed enon.59 61 analogues of capsaicin such as NE19550 and In summary, the evidence relating NO to NE21610 have been shown to have less agonistic nociception suggests a complex interrelation- activity7475 and yet retain analgesic as well as anti- ship between it and other mediators involved in inflammatory activity. It therefore seems likely the generation and maintenance of hyperalge- that capsaicin analogues with desirable features sia. The development of inhibitors which are can be developed into analgesics of the future more selective for the neural form of nitric (fig 4). oxide synthase, including ones which are restricted in their action to the periphery, will Tachykinin receptor antagonism aid in clarifying the role of NO in nociception. Among the most extensively studied of the potential nociceptive mediators within the CNS are tachykinins, a class of neuropeptides Capsaicin analogues including substance P, neurokinin A, and neu- Capsaicin is the major pungent extract from rokinin B. Ofthese, substance P has been most hot peppers of the capsicum family. It has the extensively investigated with respect to unique property of selectively activating nociceptive mechanisms. There are three polymodal nociceptors following local or receptor types, NK-1, NK-2, and NK-3; systemic administration. It has long been substance P acts preferentially on the NK- 1 established that large systemic doses of capsai- receptor.76 Substance P is located in sensory cin in the neonatal and adult animal are neuro- neurones and is released from their central ter- toxic to small unmyelinated Cfibres6" and these minals in the superficial laminae in the dorsal high dose treatments lead to a very long lasting hom of the spinal cord.77 It both directly depo- http://ard.bmj.com/ or even permanent increase in nociceptive larises dorsal hom neurones and enhances the thresholds. However, lower doses of capsai- responsiveness of cells in the dorsal horn to an cin result in an acute reversible antinociceptive excitatory amino acid, NMDA, known to be effect, distinct from the toxic effects seen with involved in the transmission of nociceptive much higher doses.6566 information. In particular, the phenomenon The pharmacological and physiological basis known as "wind up", characterised by an for the acute antinociceptive activity remains increase in the excitability of dorsal horn neu- on October 1, 2021 by guest. Protected copyright. unclear but may well be related to the action of rones following repetitive C fibre stimulation, capsaicin on neuronal ion channels. In particular, activation of cation specific ion channel causes initial depolarisation followed by an 0 inactivation of voltage gated calcium channels and a subsequent reduction ofcalcium coupled neurochemical release from either the Capsaicin peripheral or central terminals of the sensory neurones.67 Such a mechanism may underlie the short lasting (two to four hour) HO H Olvanil antinociceptive and anti-inflammatory actions of capsaicin observed with acute systemic applications. With higher or more prolonged 0 administration of capsaicin other mechanisms Nuvanil may be responsible for the loss of sensitivity to 2,NH2 both capsaicin and other stimuli, probably involving receptor desensitisation, an impair- ci ment of signal transduction, or conduction HO block in the sensory nerve fibre, or a combina- HOZ2C) H- Capsazepine tion of these.'M 68 It is likely that capsaicin acts on a specific receptor, localised to sensory neu- Figure 4 The structures ofcapsaicin and two analogues rones, and studies with the first competitive olvanil (NE 19550) and nuvanil (NE 21610) which retain the anti-nociceptive properties ofcapsaicin but show capsaicin antagonist, capsazepine, have much reduced agonist activity. Capsazepine is thefirst supported this hypothesis.69 example ofa competitive antagonist ofcapsaicin. 720 Perkins, Dray

is reduced by NK-1 receptor antagonists, sug- NMDA antagonists are given.90 Similar gesting that substance P is involved in the symptoms have also been seen in man when an underlying mechanism.78 NMDA antagonist was given intrathecally to Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from The pharmacology of tachykinins with relieve neuropathic pain.9" respect to nociception appears to differ Although the best evidence for EAA in noci- between acute and persistent nociceptive ception relates to central mechanisms, there conditions. In acute nociception, NK-2 recep- have also been studies suggesting an tors appear to be the predominant receptor involvement of peripheral EAA receptors in involved, with the endogenous mediator being nociceptor activation. Thus functional non- NKA rather than substance P. Thus NK-1 NMDA receptors (kainate/AMPA) have been antagonists are less effective in acute nociceptive demonstrated on C fibre nociceptors in vitro, models than NK-2 receptor antagonists such as and the depolarisation of spinal neurones MEN10376 and L659874.7879 In persistent following peripheral kainic acid application inflammatory hyperalgesia, however, it is was blocked by spinally applied morphine.92 93 substance P acting on the NK-1 receptor that This raises the possibility that peripherally is primarily involved, with a corresponding released glutamate or a related amino acid may upregulation of mRNA for this receptor contribute to the activation or sensitisation of subtype. nociceptor terminals, in which case a peripher- An important advance in this field has been ally acting receptor antagonist may be the development of non-peptide antagonists analgesic. for tachykinin receptors, particularly the NK-1 It may prove impossible to separate the subtype. In functional tests these antagonists, undesirable side effects of centrally active such as CP96345 and RP67580, are NMDA antagonists from their anti-nociceptive anti-nociceptive in models of persistent hyper- properties, but if this can be achieved there is algesia.80 81 The emergence of these non- the prospect of a novel class of analgesics with peptide tachykinin antagonists gives rise to the efficacy in both acute and chronic pain. On the prospect of a novel class of centrally acting, other hand further work is needed to orally available analgesics. Several of these characterise the peripheral EAA receptors and compounds are undergoing clinical trials at to develop novel antagonists without the asso- present. ciated side effects seen with centrally acting agents. Excitatory amino acid receptor In conclusion, great progress has been made antagonism in understanding the changes occurring in Excitatory amino acids (EAA), and in particu- nociceptive pathways during chronic pain con- lar glutamate, play a pivotal role in the ditions. This has caused a fundamental shift in transmission of nociceptive signals within the the way that pain therapy and the development dorsal horn of the spinal cord. Glutamate is of analgesic drugs are being directed. one of the major neurotransmitters of sensory Mechanistic studies have brought to light a

fibres, being released from C fibre afferents in number of new targets both in the periphery http://ard.bmj.com/ response to noxious stimuli, and it therefore (B1 receptors, COX-2, nitric oxide synthase) mediates the first transmission step in the neu- and in the CNS (nitric oxide synthase, ral nociceptive pathway. Consequently, antago- NMDA, tachykinin receptors). This has stimu- nism ofthis class ofneurotransmitters has been lated the development of antagonists for an obvious and attractive target for novel anal- specific kinin receptors, selective COX-2 gesic drugs. inhibitors, and capsaicin analogues which

EAA are hyperalgesic when applied intrathe- block the activity in fine afferent fibres. In the on October 1, 2021 by guest. Protected copyright. cally and induce behavioural responses such as CNS, there are various opportunities to biting and scratching suggesting an algesic develop NK1 receptor antagonists and to over- reaction; these responses are inhibited by come the difficulties associated with the antagonists at EAA receptors.82 83 Of particular present generation of NMDA antagonists. interest in recent years has been the role of the Such developments will inevitably supplement NMDA receptor (upon which glutamate acts) or replace the traditional use of NSAID and in the increase in spinal hyperexcitability opioids in the treatment of pain produced by persistent noxious input into the spinal cord and associated with chronic pain. This phenomenon ofwind up has already been 1 von Korff M, Dworkin SF, Le Resche L. Graded chronic pain states: an epidemiological evaluation. Pain 1990; referred to and it is clear that NMDA receptors 40:279-91. play a key role in the generation and 2 Dray A, Urban L, Dickenson A H. Pharmacology of chronic (84 NMDA pain. Trends Pharmacol Sci 1994;15:190-97. maintenance ofthis state."8) receptor 3 Woolf CJ. The dorsal horn: state-dependent sensory antagonists such as D-AP5, CPP, MK801, and processing and the generation of pain. In: Wall P D, and Melzack R, eds. Textbook of pain, 2nd ed. Edinburgh: more recently memantine, inhibit wind up Churchill-Livingstone, 1994: 101-12. have been shown to be anti-nociceptive in ani- 4 Bhoola KD, Figueroa CD, Worthy K. Bioregulation of mal models of persistent hyperalgesia and neu- kinins: kallikreins, kininogens and kininases. Pharmacol Rev 1992;44: 1-80. ropathic pain.85"9 However, a major drawback 5 Hall JM. Bradykinin receptors: pharmacological properties in the development of such compounds as and biological roles. Pharmacol Ther 1992;56: 131-90. analgesics is the presence of unacceptable side 6 McEachern AE, Shelton ER, Bhakta S, Obernolte R, Back C, Zuppan P, et al. Expression cloning of a rat B2 bradyki- effects at, or close to, the analgesic dose. Both nin receptor. Proc NadAcad Sci USA 1991;88:7724-8. motor disturbances such as ataxia and 7 Hess JF, Borkowslki JA, Young GS, Strader CD, Ransom RW. Cloning and pharmacological characterization of a psychomimetic-like behavioural responses human bradykinin (BK-2) receptor. Biochem Biophys Res have been reported in animal models when Commun 1992;184:260-8. Novel pharmacological strategiesfor analgesia 721

8 Menke JG, Borkowski JA, Bierilo K, MacNeil T, Derrick cyclooxygenase 2 in vivo is antiinflammatory and nonul- AW, Schneck KA, et al. Expression cloning of a human B, cerogenic. Proc NadAcad Sci USA 1994;91:3228-32. bradykinin receptor. Biol Chem 1994;269:21583-6. 38 Tomlinson A, Appleton I, Moore AR, Gilroy DW, Willis D, 9 Burgess GM, Mullaney J, McNeil M, Dunn P, Rang HP. Mitchell JA, et al. Cyclo-oxygenase and nitric oxide Ann Rheum Dis: first published as 10.1136/ard.55.10.715 on 1 October 1996. Downloaded from Second messengers involved in the action ofbradykinin on synthase isoforms in rat carrageenin-induced pleurisy. BrJ cultured sensory neurones. JNeursoci 1989;9:3314-25. Pharmacol 1994;113:693-8. 10 Dray A, Patel IA, Perkins MN, RueffA. Bradykinin-induced 39 Endo T, Ogushi F, Sone S, Ogura T, Taketani Y, Hayashi Y, activation of nociceptors: receptor and mechanistic studies et al. 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