New molecules in analgesia

British Journal of Anaesthesia 1995; 75: 145–156

New molecules in analgesia H. P. RANG AND L. URBAN Analgesic therapy is currently dominated by the two main classes of analgesic drug, namely opiates and non-steroidal anti-inflammatory drugs (NSAID), which have been used clinically from the earliest phase of scientific therapeutics, which began around the beginning of the 19th century. Many improved synthetic variants have been developed, as well as improved techniques of administration, but there has been little conceptual innovation. In the field of neuropathic pain, for which NSAID are ineffective, and opiates relatively so, increasing use is now made of the analgesic effect of tricyclic antidepressants, agents that block sympathetic transmission, and agents that reduce membrane excitability (local anaesthetics and related drugs). Generally speaking, these represent new uses for old molecules. Apart from NSAID and opiate variants, new molecules designed specifically as analgesic agents have not been forthcoming, in spite of the obvious need. This is probably because of the relatively slow advance, until recently, in our understanding of the pathogenesis of chronic pain, which now distinguishes it mechanistically from the acute response to a noxious stimulus. These advances are reviewed by others in this issue and elsewhere [see 24, 73, 131, 136, 145]. In this article we examine the prospects for new drug therapies based on the mitigation of some of the physiological and neurochemical changes that occur in the nociceptive pathway after injury. Where possible, we discuss actual molecules and their properties, but there are many processes in which the target can now be defined, but where the magic bullet has yet to be invented, so the practical realization will inevitably be some years off. Even where molecules exist, it must be realized that many conditions have to be satisfied—mainly related to its specificity, pharmacokinetic and toxicological characteristics—before a new compound with appropriate pharmacological effects can achieve the status of a usable drug. The main processes that are believed to contribute to chronic pain (see fig. 1) can be divided into: (1) peripheral mechanisms leading to abnormal excitation of peripheral nociceptive afferent fibres;

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(2) central mechanisms, resulting in facilitated transmission in the dorsal horn and higher up the nociceptive pathway. The peripheral mechanisms that produce increased excitation of peripheral sensory neurones include: (a) the action of inflammatory mediators and cytokines on nociceptive nerve terminals; (b) the effect of peripheral nerve damage (axotomy or peripheral neuropathy). Pharmacological approaches targeted on peripheral mechanisms are discussed below. Facilitation in the dorsal horn occurs as a direct consequence of increased C-fibre input [73, 138]. This “wind-up” phenomenon (reviewed by Urban and colleagues [128]) is due partly to the interaction of two mediators released by the C-fibre terminals, namely glutamate, which acts on AMPA (␣-amino3-hydroxy-5-methylisoxazole) and NMDA (Nmethyl-D-aspartate) receptors and substance P, which acts on neurokinin (NK)-l receptors. Other modulating influences, whose activity may be altered in chronic pain states, include GABA-mediated inhibition, and alterations in opioid peptidemediated synaptic inhibition, due partly to increased cholecystokinin (CCK) release [111] acting in opposition to endogenous opioids. Many other peptide and non-peptide mediators are believed to modulate transmission in the nociceptive pathway. These include peptides, such as calcitonin gene-related peptide (CGRP), somatostatin, neuropeptide Y (NPY); non-peptides such as adenosine, and various amino transmitters; as well as modulators such as eicosanoids and nitric oxide. Pharmacological approaches based on these various chemical mediators acting at the spinal cord level are discussed later.

Peripherally-acting agents In this section we discuss first inflammatory mediators, kinins, prostanoids and cytokines, which directly or indirectly influence peripheral nociceptors and effectively tune the spinal input to a “crescendo” during inflammation. The receptor sites and processing enzymes for such mediators are the primary targets for drugs with analgesic activities. We also discuss drugs with direct neuronal targets, designed to reduce the excitability and H. P. RANG, MB, BS, DPHIL, FRS AND L. URBAN, MD, PHD, DSC, Sandoz Institute for Medical Research, Gower Place, London WC1E 6BN. Correspondence to H. P. R.

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Figure 1

Sites of action of analgesic drugs.

activity of nociceptive primary afferents through modulation of ion channels by direct influence or through neuronal receptors. INFLAMMATORY MEDIATORS AND INHIBITORS

Bradykinin Bradykinin (BK) and kallidin are the products of the blood clotting cascade and tissue injury, respectively.

They can also be formed by alternative routes through activation of immune cells. Both molecules contribute strongly to the events of inflammation [23], and also (acting mainly on B2 receptors) cause excitation and/or sensitization of primary afferent nociceptors leading to pain and hyperalgesia. This occurs partly through a direct action, and partly through the production and release of other compounds which act on nociceptors. Accordingly, bradykinin B2 receptor antagonists are analgesic in

New molecules in analgesia

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Figure 2 Effects of NSAID on the constitutive and inducible forms of cyclo-oxygenase (COX-1 and COX-2).

acute inflammatory conditions [44, 49, 87, 115]. Recently it has been discovered that during prolonged inflammation, B1 receptors play an important role, and B1 receptor antagonists are also able to attenuate the hyperalgesia [87]. The expression of the B1 receptor appears to be increased in inflamed tissue, though so far there is no evidence of its existence on neurones. Because of bradykinin’s prominent function in the pathogenesis of inflammatory pain, BK receptor antagonists hold promise as novel analgesic agents. Several B2 receptor antagonists have been described, mainly peptide analogues such as NPC16731, NPC567, HOE 140 and CP0127 which show antiinflammatory and analgesic activity in various animal models [114, 115]. More recently a non-peptide B2 receptor antagonist (WIN 64338) has been designed [95]. The only known B1 receptor antagonists so far are peptides, the best characterized being desArg9[Leu8]BK. This compound shows analgesic activity in chronic hyperalgesia [87]. In conclusion, B1 and B2 receptor antagonists may both prove to be useful as analgesic/antiinflammatory agents, though it will probably only be when potent non-peptide compounds are discovered that this approach will lead to drugs in the clinic. Prostaglandin and other eicosanoid antagonists Inflammatory mediators trigger arachidonic acid (AA) production in a wide array of cells, resulting in the formation of prostanoids through the cyclooxygenase (COX) pathway and leukotrienes through the 5-lipoxygenase pathway. In inflamed tissue PGE2 and PGI2 (prostacyclin) are produced in excess. Recently two isoforms of the COX enzyme were described [129, 139]. The constitutive form (COX-1) is present in different tissues and its function is essential for the electrolyte balance in the kidney [139] and for the cytoprotection of the gastric mucosa [132]. The inducible isoform (COX2) plays the major role in inflammatory conditions (fig. 2). Induction is stimulated by lipopolysaccharides (LPS) [63] and bacterial toxins [75], and occurs in vivo in carrageenan-evoked inflammation [9, 105]. Management of inflammatory pain conditions relies heavily on NSAID which inhibit the formation of prostaglandins and leukotrienes by a non-selective inhibition of the COX isoforms. Some of their unwanted effects, particularly those on the gastric

mucosa and the kidney, are believed to be associated with inhibition of COX-1, so there is great interest in the possibility of developing selective COX-2 inhibitors, which should show a better side-effect profile. Prototype selective COX-2 inhibitors, such as L-745,337 and SC-58125 block hyperalgesia and plasma protein extravasation in carrageenan-induced inflammation in the rat without any gastrointestinal or renal side effects [9]. The alternative branch of the arachidonic acid cascade (lipoxygenase) produces leukotrienes, some of which, for example leukotriene B4 (LTB4) and 8R,15S-diHETE (8R,15S-dihydroeicosatetraenoic acid), have been shown to sensitize mechano- and thermoreceptors upon intradermal injection [70]. A novel LTB4 receptor antagonist, CP-105,696 was reported to attenuate the progression of collageninduced arthritis [45]. Although the general clinical symptoms and histological changes were dramatically reduced by CP-105,696, at present there is no evidence of its analgesic activity. Cytokines Cytokine release from immune cells is part of the early host-defence reaction in inflammation [20]. Interleukin-1␤ (IL-1␤), IL-8 and tumour necrosis factor ␣ (TNF-␣) are potent hyperalgesic agents in animal models owing to their ability to stimulate production and release of other pro-inflammatory agents [35, 40]. The hyperalgesia induced by IL-1␤ depends partly on induction of bradykinin B1receptors [15]. Ferreira and colleagues [35] showed that the peptide Lys-D-Pro-Thr, an IL-1 ␤ antagonist, was able to block inflammatory hyperalgesia. This is an interesting approach, though it has not yet led to compounds for potential clinical use. Cytokine (IL-1 and TNF-␣) production is regulated at the transcriptional and translational level, and compounds (known as cytokine-suppressive anti-inflammatory drugs, or CSAID), are now being discovered which inhibit their production. One of these, SKF 86002, inhibits LPS-induced interleukin production and shows analgesic activity in acute and chronic pain models [61]. Recently the target of this drug has been identified and cloned as a pair of novel serine/threonine protein kinases [62]. CSAID, designed to block the activity of these kinases, may provide new analgesic/anti-inflammatory drugs for clinical use.

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British Journal of Anaesthesia Table 1 Current uses of sodium channel blocking drugs as systemic analgesics Drug Local anaesthestics: Lignocaine

Tocainide Anticonvulsants Carbamazepine Phenytoin sodium Antiarrhythmics: (see also Lignocaine) Mexiletine

Indication

Reference

Chronic pain (rev.) Neuropathic pain Postoperative pain Postherpetic neuralgia Trigeminal neuralgia

Swerdlow [118] Tanelian and Borse [122] Tverskoy et al. [126] Rowbotham et al. [93] Lindstrom and Lindblom [66]

Neuropathic pain Trigeminal neuralgia Chronic pain

Tanelian and Brose [122] Taylor et al. [123] Swerdlow [117]

Neuropathic pain

Tanelian and Brose [122] Chabal et al. [11] Dejgard et al. [21]

Diabetic neuropathy

MODULATION OF ION CHANNELS

Drugs acting at sodium channels In addition to their normal role in excitable membranes, which underlies the generation and propagation of action potentials in nerve and muscle cells, there is evidence that abnormal sodium-channel function may be important in neuropathic pain—a clinical category that is often resistant to conventional analgesic drugs. Studies, mainly by Devor and colleagues [17], have shown that spontaneous ectopic activity develops in damaged sensory neurones, originating both at the site of the neuroma (if present) and in the cell body. It is suggested that this results from abnormal accumulation of sodium channels in the cell membrane. The effectiveness of anticonvulsants, local anaesthetics and antiarrhythmic drugs in the treatment of certain types of pain (particularly neuropathic [68, 122]) probably reflects the fact that they are all sodium-channel blockers [10, 89, 104]. Lignocaine selectively blocks ectopic discharges originating from experimental neuromas, without affecting axonal conduction [19], and this may be a general feature of these drugs. There are various possible explanations for this selectivity: (1) Ectopic discharges may originate as the consequence of increase in the number of sodium channels on DRG cells [18, 71], and blockers may act at sites of ectopic discharge by simply reducing the number of active sodium channels below the threshold needed for spontaneous activity. (2) The activity-dependent action of many sodium channel-blocking drugs [92] may result in inhibition of the tonic ongoing discharge at concentrations too low to interfere with action potential condution under physiological conditions. (3) The sodium channels expressed at the site of ectopic discharge may be a different molecular species from normal sodium channels, and more sensitive to certain blocking drugs. It has been reported recently that type III sodium channel mRNA (normally expressed only during embryonic development) is expressed in DRG cells after axotomy [130]. These findings open the possibility of developing new types of sodium channel-blocking drugs specifically for use in neuropathic pain states, in addition to those listed in Table 1. Nociceptive sensory neurones under normal condi-

tions express at least two types of sodium channel, a tetrodotoxin (TTX)-sensitive, fast-activating type that is found in all sensory neurones, and a tetrodotoxin-resistant, slow-activating type found only in the class of small diameter slow-conducting cells which includes polymodal nociceptors [56, 83, 91]. The slow TTX-resistant channel, because of its selective expression by nociceptivie afferent neurones, offers an attractive drug target for novel analgesic drugs, but nothing is yet known about its sensitivity to known sodium channel-blocking drugs. Modulation of potassium channels In general, opening of potassium channels results in membrane hyperpolarization, and inhibition of membrane excitability, an effect which might be exploited in analgesia. Two of the many known types of potassium channels have attracted most attention in recent years, namely the large-conductance calciumdependent potassium channel (maxi-K channel), and the ATP-sensitive potassium channel [27]. The maxi-K channel has partcularly interesting features from the point of view of neuronal hyperexcitability. These channels are present in high density in many neurones (as well as in smooth muscle cells) though in sensory neruones they are activated only at relatively high intracellular calcium concentrations [82] and their functional significance is not clear. The voltage and calcium sensitivity of these channels means that they are activated after the action potential, producing an afterhyperpolarization that limits the firing frequency of the cells. Activators of these channels therefore represent a possible approach to new analgesic drugs. Dehydrosaponins, extracted from Desmodium adscendens [74] and more importantly substituted benzimidazolones (NS 004 and NS 1619) are potent maxiK-channel openers, but they lack selectivity as they simultaneously block other membrane channels [26]. NS 1619 was found to inhibit presynaptic calcium signals and transmitter release from peripheral sensory nerves in the airways [106, 116]. Cromakalim, pinacidil and aprikalim, compounds with diverse chemical structure, can activate type I ATP-sensitive potassium channels in various tissues, including neurones [27]. There have been no reported studies of the analgesic effect of the maxi-K or ATP-sensitive potassium channel openers, so

New molecules in analgesia their potential usefulness in this indication remains to be assessed. For practical purposes, it will be necesary to identify drugs which lack the powerful cardiovascular actions of the current generation of compounds. OTHER MECHANISMS

Peripherally-acting opiates In addition to the well established central analgesic effects of opiates, recent studies revealed that immune cells could produce endogenous opiates during inflammation [98]. This production of opioids is matched by increased expression of different opiate receptors on primary afferent nociceptors, where they can exert analgesic activity [14]. Experiments performed in several models of inflammatory and neuropathic pain suggest that the antinociceptive effect of opiates is due, at least partly, to their action on primary afferent nerve terminals [1, 54] and sympathetic fibres [120]. Bradykinininduced mechanical hyperalgesia is attenuated by agonists at ␮-, ␬-, or ␦-opioid receptors injected locally, these effects being prevented by naloxone [120]. In in vitro experiments, ongoing activity in Cfibres innervating inflamed tissue can be inhibited by ␮- or ␬-receptor agonists [1]. These data suggest that both primary afferent nociceptors and sympathetic fibres could be targets for opiates and raises the possibility of developing peripherally acting opiates as analgesics which would lack the sedative and psychotropic effects of existing opiates, as well as avoiding the dependence problem [108, 113].

Centrally-acting agents In this section we focus first on neuropeptides that have modulatory or transmitter functions in the nociceptive pathway, whose receptors or processing enzymes offer potential targets for new types of analgesic drugs. We then discuss briefly other mediators and targets, namely excitatory amino acids, nitric oxide, eicosanoids and adenosine. NEUROPEPTIDES AND NEUROPEPTIDE ANTAGONISTS

Tachykinins and CGRP in the nociceptive pathway The tachykinins are a family of neuropeptides which include the biologically important mammalian tachykinins, substance P (SP), neurokinin A (NKA) and neurokinin B (NKB). There are three major types of tachykinin receptors (NK-1, NK-2 and NK-3) which recognize these peptides [81], SP being the preferred agonist at NK-1 receptors [67]. In the human CNS, NK-1 receptors predominate and are believed to play a major role in pain transmission. Tachykinins, particularly SP, the most intensively studied sensory neuropeptide, are known to be important mediators in the nociceptive pathway [65, 73, 85, 90]. SP is released, along with NKA, in the spinal cord in vivo upon noxious peripheral stimulation [25, 43, 124]. In acute nociception, NKA, acting on NK-2 receptors, appears to play the major role. NK-1 antagonists have only a small effect

149 on the slow exictatory synaptic potential in the spinal cord elicited by C-fibre stimulation, whereas NK-2 antagonists are much more effective [38, 80], suggesting that, under normal physiological conditions, SP is less important than other excitatory transmitters (particularly NKA), in this pathway. Accordingly NK-1 receptor antagonists produce only a weak inhibition of acute nociceptive responses. In models of pathological pain (particularly those involving inflammatory hyperalgesia) NK-1 receptors become increasingly important [72, 125]. NK-1 receptors are upregulated during hyperalgesic conditions [72, 99] and the production and release of tachykinins from primary afferent fibres also increase [22, 72, 100]. In the spinal cord the parallel increase in the amount of SP released and in the number of NK-1 receptors both contribute to the enhancement of SP-mediated transmission. Substance P produces long-lasting depolarization of dorsal horn neurones [79, 127]. This contributes to the long-lasting facilitation of transmission (“windup”) in the nociceptive pathway that follows activity in peripheral nociceptive neurones [128]. Facilitation of nociceptive transmission is believed to be a major factor in producing functional hyperalgesia; indeed chronic pain and hyperalgesia are always associated with an increased excitability of spinal neurones [50]. Peptide antagonists specific for NK-1 and NK-2 receptors have been known for several years, and used to study the functional role of these receptors, but have not been developed for therapeutic use. An important breakthrough came when Snider and colleagues [109] reported the first non-peptide NK1 antagonist, CP 96345, which showed good oral activity in a range of animal models. Several more such compounds have subsequently been reported [33, 34, 39, 42]. The first compound of this type, CP 96345, which has been the most widely studied, has a significant blocking effect on calcium channels, which resulted in cardiovascular side effects, and partly accounted for its analgesic properties. This side effect, which complicated the interpretation of the analgesic effects in terms of NK-1 receptor antagonism, has been eliminated in subsequent compounds of this type. Enhanced spinal excitability produced by SP or by electrical or natural noxious stimulation is inhibited by non-peptide NK-1-receptor antagonists [88, 141]. NK-1-receptor antagonists are also antinociceptive in various animal models in which hyperalgesia is allowed to develop, for example adjuvantinduced arthritis models [6, 32, 42, 77, 144]. In the formalin model, the irritant response to an injection of formalin into the paw of a rat shows two distinct phases; the first phase (lasting for about 10 min) is unaffected by NK-1 antagonists, whereas the second phase (lasting for about 60 min, and representing the phase of spinal hyperexcitability), is strongly inhibited. A recent study has shown that the hyperalgesia which develops in rats with experimental diabetes, a model for clinical neuropathic pain, is inhibited by RP-67580, a selective NK-1 antagonist [13]. Substance P also has various functions in the periphery, contributing to inflammation, immune

150 cell activation and the activity of secretory and smooth muscle cells in different organs (for review, see Maggi and colleagues [67]). Thus, the therapeutic indications for tachykinin antagonists may be much broader than simply analgesia. Migraine has been described as a neurogenic inflammatory process in intracranial (meningeal) blood vessels, primarily triggered by trigeminal nerve activation [69]. Neuropeptides (SP and CGRP) released from these afferents cause vasodilatation and plasma protein extravasation and, in addition, amplify these inflammatory processes by stimulating the release of bradykinin and other inflammatory mediators from non-neuronal cells. NK-1-receptor antagonists strongly inhibit the leakage of plasma protein from dural blood vessels in response to trigeminal nerve stimulation [64, 78, 107], a model for the acute migraine attack. Though tachykinins and tachykinin receptors are widely distributed in the central nervous system, NK-1 antagonists have not so far been reported to have marked effects on CNS function, apart from their analgesic action and an anti-emetic effect [41], so there is hope that such drugs will be relatively free of unwanted effects compared with the currently available analgesic drugs. Clinical trials of several non-peptide NK-1 antagonists are currently in progress, and such drugs should soon become available for more general clinical use as analgesics. Other neuropeptides In addition to the neurokinins, many other peptides are released by primary afferent nociceptive neurones [60], though little is known so far about their functional role. The expression of several of these peptides changes under pathological conditions, such as axotomy or peripheral inflammation, which are associated with clinical pain states. It is therefore reasonable to expect in the future that new drugs able to influence the synthesis, release or degradation of some of these peptides, or to act as mimetics or antagonists at their receptors, will have a role in pain therapy. At present, there are only a few clues as to which peptides are likely to offer promising drug targets. Calcitonin gene-related peptide. CGRP is released by nociceptive afferent fibres in the dorsal horn in response to noxious stimuli [76]. It produces slow depolarizing responses in dorsal horn neurones, and also potentiates the depolarizing effect of SP. Intrathecal administration of a neutralizing antibody to CGRP produces an antinociceptive effect [59], suggesting that an effective receptor antagonist might have useful analgesic properties. Unfortunately, in contrast with the situation with SP, the only CGRP antagonist known is a large peptide, CGRP8–37, which has not yet been assessed by the intrathecal route. Non-peptide antagonists at CGRP receptors have not yet been reported. In contrast with SP and CGRP, which are excitatory neuropeptides, where a receptor antagonist is likely to have analgesic properties, other

British Journal of Anaesthesia sensory neuropeptides have mainly inhibitory actions in the dorsal horn. Three in particular, somatostatin, cholecystokinin and galanin, have recently been the subject of considerable investigation. Somatostatin. Somatostatin along with its stable peptide analogues, octreotide and vapreotide, produce analgesia in various animal models, and are also effective in humans after intravenous, epidural or intrathecal administration [5]. Somatostatin analogues generally show affinity for opioid receptors, and in some studies their analgesic effects are reported to be reversible by naloxone, so it is not clear whether they cause analgesia by acting specifically on somatostatin receptors, or as surrogate opioids. Studies in rats have shown significant neurotoxicity after spinal administration of somatostatin, leading to motor dysfunction, but this has not been reported with the synthetic analogues. Currently only peptide analogues of somatostatin, which do not reach spinal sites unless given intrathecally or epidurally, have been described. None the less there are several reports showing that octreotide produces analgesia in humans when given systemically [86, 101, 134]; the mechanism of its action remains unclear. Cholecystokinin. CCK differs from most of the other neuropeptides that modulate nociceptive transmission in that it appears to act, not directly, but by interaction with the opioid system; it can be regarded as an endogenous inhibitor of opioid-mediated analgesia [2, 111]. CCK given intrathecally antagonizes the analgesic effect of opiates acting on the ␮receptor, but does not by itself produce hyperalgesia under normal conditions. Under conditions of stress, however, when the endogenous antinociceptive opioid systems are activated, CCK produces hyperalgesia, similar to that produced by naloxone. Conversely, CCK antagonists, such as L365260 and CI988, enhance the analgesic effect of opiates [2, 112]. This accentuation is clearly evident in normal animals, but under conditions of chronic inflammation, in which the antinociceptive potency of morphine is enhanced compared with the normal situation, CCK antagonists have no effect. It is postulated that the release of endogenous CCK is inhibited under these conditions, so that the “CCKbrake” on opioid action is removed, and antagonism of CCK at the receptor level is without effect. Many neuropathic pain states are associated with hyperalgesia and allodynia that is relatively resistant to opiates. It is suggested [111, 140] that this results from increased release of CCK, since CCK antagonists enhance the effect of morphine in animal models of neuropathic hyperalgesia. The antagonists L365260 and CI988 are selective for the CCKB receptor, which is found in the central nervous system of rodents. In the primate spinal cord, the CCKA receptor predominates, so for use in primates CCKA antagonists, such as devazepide or nonselective antagonists, such as lorglumide [135] are theoretically preferable. Such drugs are being developed for clinical use. Though they are unlikely to

New molecules in analgesia be useful as analgesics on their own, they may usefully enhance the analgesic potency of opiates without increasing the respiratory depressant and other unwanted effects. Galanin. Galanin [4] is another neuropeptide released by nociceptive afferent neurones. Unlike SP and CGRP, the synthesis of galanin is upregulated by peripheral nerve damage, and it is postulated [133] that it exerts a tonic inhibitory effect on transmission in the dorsal horn. Galanin-like agonists would therefore be a possible strategy for developing new analgesic drugs.

OTHER APPROACHES

Excitatory amino acid antagonists Antagonists at NMDA receptors, such as AP-5 and dizocilpine (MK801), prevent the phenomenon of “wind-up” in the spinal cord [46, 137], which is believed to play an important role in inflammatory hyperalgesia [143], and show analgesic activity in various animal models when administered intrathecally. New NMDA-receptor antagonists are being developed for various indications, including ischaemic brain damage, head trauma and epilepsy, but their use as analgesics may be limited by unwanted side effects, particularly psychotomimetic effects and motor disturbances. A recent clinical study [58] showed that an NMDA-receptor antagonist, CPP, given intrathecally to a patient with severe neuropathic pain, reduced the tendency for mechanical stimulation to produce progressively worsening pain (presumed to reflect the “wind-up” phenomenon) though it did not affect the resting pain level. The patient, however, developed marked anxiety and hyperacusis, and studies in rats [57] showed that there was little margin between doses needed for antinocieptive effects and those causing motor paralysis, so this approach does not appear to be very promising at present. Ketamine, a dissociative anaesthetic which (like MK801) blocks the ion channel associated with the NMDA receptor is effective as an analgesic agent, given on its own or as an adjunct to morphine [28, 48]. Another clinically available drug, the antiviral agent memantine, also possesses NMDA-blocking activity, and has been shown to be antinociceptive in the formalin test in rats, with a reasonable margin between this action and disturbance of motor function [31]. The analgesic activity of this drug in humans has not yet been reported. Though blocking NMDA-receptor function appears, in principle, to be an attractive approach to new analgesic agents, experience so far has been disappointing because the selectivity of existing drugs for the nociceptive pathway is insufficient for analgesia to be produced without major unwanted effects.

Adenosine analogues There is considerable evidence suggesting that adenosine exerts a modulatory effect on nociceptive

151 transmission both in the periphery and in the central nervous system [96]. Adenosine receptors fall into two main classes, A1 and A2. A1 receptors mediate predominantly inhibitory effects on synaptic transmission, whereas A2 receptors are mainly excitatory. Both receptor types are expressed in the central nervous system, and both types occur in the superficial region of the dorsal horn, where they are believed to be present on small interneurones. Intrathecal administration of adenosine analogues produces a powerful antinociceptive effect [52, 53, 96], though this is often accompanied by motor impairment. Systemic administration of adenosine agonists is also effective [51], but is accompanied by cardiovascular effects (hypotension and cardiac depression). Studies with receptor-selective agonists suggest that the antinociceptive action results from activation of A1 receptors, which are known to exert pre- and post-synaptic inhibitory effects in the dorsal horn. The physiological role of adenosine modulation of nociceptive transmission is not well understood, though there is some evidence that opioid actions may be mediated in part through the release of adenosine. Thus, adenosine receptor antagonists inhibit the antinociceptive effects of morphine, and morphine has been shown to elicit adenosine release [97]. Furthermore, A1-receptor agonists act synergistically with opiates when both drugs are given intrathecally. Adenosine analogues also affect nociceptive transmission through an action in the periphery. Adenosine produces pain after administration to the blister base in human subjects [7] and causes mechanical hyperalgesia in the rat when injected locally. This results from A2-receptor activation, which can be blocked by the selective A2 blocker, PD 081360-0002 [119]. On the other hand peripheral application of the A1-receptor agonist analogue Rphenylisopropyl-adenosine (R-PIA [102, 103]) prevents paw licking in mice after formalin injection [51]. At both central and peripheral sites, therefore, A1 receptors mediate antinociceptive effects, whereas A2 receptor agonists have the opposite effect. These findings suggest the possibility that selective A1-receptor agonists might prove to be useful analgesic agents, either as systemic agents, provided that the problems of cardiovascular side effects and effective penetration into the central nervous system can be overcome, or for use as intrathecal or epidural agents, possibly in combination with opiates. An alternative approach is suggested by the work of Keil and DeLander [55], who showed that spinal administration of the adenosine kinase inhibitor, 5⬘amino5⬘deoxyadenosine, which inhibits the degradation of endogenous adenosine, produces an antinociceptive effect. Adrenoceptor agonists The analgesic action of clonidine, an alpha2adrenoceptor agonist, has been known for many years [142], and it is sometimes used by systemic or intrathecal administration for this purpose [8, 29, 30], usually in combination with other agents. The main disadvantages are sedation and hypotension.

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Table 2 Summary of potential new drugs in analgesia (COX, cyclo-oxygenase; CSAID, cytokine-suppressive anti-inflammatory drugs; CGRP, calcitonin gene-related peptide; CCK, cholecystokinin; NMDA, N-methyl-D-aspartate) Short/medium term

Long term

Target

Notes

Target

Notes

Selective COX-2 inhibitors

Prototype compounds

Leukotriene antagonists

Prototype compounds

Bradykinin B2/B1-receptor antagonists CSAID

NK-1 receptor antagonists

Several compounds in development

Non-peptide compounds needed for therapeutic use Prototype compounds known—IL-1 antagonists and agents that inhibit cytokine production Specificity for nociceptive neurones not yet achieved No non-peptides known Peptide analogues available. No nonpeptides known No non-peptides known

Peripherally-acting opiates CCK-A and/or B receptor antagonists Adenosine A1 receptor agonists Novel alpha2-adrenoceptor agonists

Several compounds in development Compounds in development

Novel Na-channel blockers and K-channel openers CGRP-receptor antagonists Somatostatin-receptor agonists Galanin-receptor agonists

Prototype compounds

NMDA-receptor antagonists Nicotinic-receptor agonists

Used topically, as a transdermal patch, clonidine has also been reported to relieve hyperalgesia in patients with sympathetically-mediated pain, possibly by acting presynaptically on sympathetic nerve terminals in the skin [16]. Dexmedetomidine, an alpha2-receptor agonist used in veterinary anaesthesia, is more potent in antinociceptive assays than clonidine when given intrathecally, but produces similar motor disturbances, and appears to offer little advantage [36]. The mechanism of action of alpha1-receptor agonists is thought to involve inhibition of SP release from primary afferent neurones [84, 121], though they also appear to exert a postsynaptic inhibitory effect on dorsal horn neurones [47]. Recently, a novel alpha2-receptor agonist, S 12813-4, was shown to produce analgesic effects in animal models [54], and to inhibit the release of SP from the spinal cord [12]. There is some reason to believe that the antinociceptive effects of alpha2-receptor agonists may be mediated by a specific subtype of the receptor, so there is a possibility of finding a new agent which will act more selectively, and thus avoid the unwanted hypotension and sedation that occurs with clonidine.

Future trends

Epibatidine

References

Recent excitement was generated by the discovery that epibatidine, a compound isolated from the skin of an Ecuadorean frog, showed extremely potent antinociceptive activity in rats and mice [110], active at doses of 1–5 ␮g kg91. The potency of epibatidine in tail-flick or hot-plate assays is roughly 100 times that of morphine, but it is not blocked by naloxone. Further studies [3, 94] have shown that epibatidine is a very potent nicotinic agonist, and that this action accounts for its antinociceptive activity. Unfortunately, at doses only slightly larger than those that inhibit nociceptive reflexes, epibatidine produces motor disturbance and autonomic effects [37], so it is unlikely that it can be developed as an analgesic drug, though it is possible that analogues will be discovered with a superior profile.

Several compounds known. Side effect problem may not be surmountable Several compounds known. Side effect problem may not be surmountable

The evidence of functional and structural changes, often maladaptive, which underlie chronic pain in animal models is probably applicable to human pain syndromes, and should lead to the introduction of drugs based on new mechanistic principles. At the same time, the clarification of the mechanisms involved in the establishment of chronic pain conditions, in which the pain persists even though the precipitating cause has disappeared, should enable existing therapies to be targeted more precisely, as well as revealing new targets for drug discovery. Many of these will be “conventional” targets—receptors, enzymes, transport systems, channels, etc. However, we can also look forward to the targeting of regulatory events at the level of gene transcription, which are known to be important in the adaptive changes in the nociceptive pathways thought to underlie chronic pain; therapeutic intervention at this level cannot yet be attempted, but will become increasingly feasible as the biochemical control of transcription becomes better understood. Table 2 summarizes some possible new developments in the short/medium term (introduction possible within 5 years) and in the longer term.

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