61

Pain, 41 (1990) 61-69 Elsevier PAIN 01573

Basic Section Review A rticle

Capsaicin: actions on nociceptive C-fibres and therapeutic potential Bruce Lynn Department of Physiology, University College London, London (U.K.)

(Accepted 13 December 1989)

Recent work on the excitatory action of capsaicin on somatic and visceral afferent neurones shows that depolarizaSummary tion is selective for C-fibre polymodal nociceptor afferents and involves opening a non-selective cation channel. Exposure to significantly suprathreshold amounts of capsaicin causes permanent degeneration of C-fibre afferents in adult rats. Functional changes in rats (h~algesia, di~~sh~ neurogenic inflation) are likely to be a direct consequence of the loss of C-fibre nociceptors, and so are the reductions in neuropeptide levels that follow adult capsaicin treatment. Clinical trials of topical capsaicin treatment for post-herpetic neuralgia have yielded promising results. The selective nature of the action of capsaicin in reducing just C-nociceptor activity may make it particularly useful for treating pain states triggered by C-fibre input. Key words: Pain: C-fibre; Polymodal nociceptor; Post-herpetic neuralgia; Cap&&

Introduction This review will concentrate on 3 areas, (1) the immediate excitatory action of capsaicin on a sub-pop~ation of afferent neurones, (2) the question of how far the long-term functional changes that follow capsaicin treatment in adult rats depend on actual C-fibre degeneration rather than just on peptide depletion, and (3) the use of capsaicin in treating chronic pains of peripheral origin. Actions on neurones innervating the skin in adult mammals will be reviewed in most detail. Capsaicin also has major effects on other somatic and visceral afferents and these have been reCorrespondence to: Dr. 3. Lynn, Department of Physiology, University College London, Cower St., London WClE 6BT, U.K.

viewed in detail by Maggi and Meli [%I. The actions of capsaicin on neonatal rats were extensively studied in the late 70s and early 80s and have been thoroughly described in several reviews [e.g., 18&O]. The reductions in nociceptive behavioural responses in neurogenic inflammation and in neuropeptide levels in rodents following systemic administration of capsaicin have also been extensively reviewed [31,11,18,60] and will not be covered here.

Immediate actions of capsaicin on afferent neurones (1) Ex~i~a~i~~ of affluent t~rrni~~~~

The ‘hot’ sensation caused by peppers is, of course, due to excitation of afferent nerve endings

0304-3959/90/$03.50 0 1990 Elsevier Science Publishers B.V. (Biomedical Division)

in the oral mucosa by capsaicin. Similar excitatory actions occur in the skin, in the airways and in many visceral organs. This widespread irritancy is due to a highly selective excitation of a sub-class of somatovisceral afferents with unmyelinated (C-fibre) axons. In the skin, nociceptive C-fibres of the polymodal (or ‘mechano-heat’) class are excited in all mammalian species tested, including cat [23]. rabbit [76] and rat [42.77]. Most other types of C-fibre afferents, e.g., sensitive C-mechanoreceptors or cold-sensitive thermoreceptors, are not excited. However. excitation of warm-sensitive thermoreceptors has been reported [23]. A-fibre afferents are generally unaffected by capsaicin. although the relatively uncommon AS mechanoheat nociceptors in rat hairy skin are excited [77]. I)

Depolurisution of ufferent fihres und cell bodies Excitation of afferent terminals requires local depolarisation, but it is not possible to study the small afferent terminals directly with microelectrodes because they are buried within the tissues that they innervate. Instead, studies of capsaicin’s depolarising action have been carried out on axons in nerve trunks or on the cell bodies of appropriate ganglia (e.g., dorsal root ganglia, nodose ganglion). Capsaicin causes a graded depolarisation of axons in the rat sciatic [28] and vagus [58] nerves and somata from rat nodose [58] and dorsal root [3.30] ganglia. Depolarisations were only seen in a sub-population of ganglion cells with axons conducting in the C-fibre range [30,58] and nerve depolarisations were greatly reduced in preparations from rats treated neonatally with capsaicin, and so depleted of C-fibres [28]. Both these lines of evidence indicate that, as with its excitatory action, capsaicin is only acting on a sub-population of C-afferent neurones. The depolarisation produced by capsaicin is due to a non-specific increase in cation permeability. Of the common extracellular cations, both sodium and calcium show greatly increased permeability [58.85]. In rat dorsal root ganglion (DRG) cells under voltage clamp, capsaicin produces an inward current at negative holding potentials, the current voltage relation is linear (i.e., the conductance change is not voltage depen-

dent). and the reversal potential is 0 mV (indicating no specificity between major intracellular and extracellular cations) [lo]. The channels opened by capsaicin in rat DRG cells have recently been studied using patch clamp techniques [21]. Single channel conductance is calculated as 20 pS with other properties as expected from whole cell recordings. These capsaicin-gated channels appear to differ from previously described channels in DRG membrane. Similar channels are opened in the same sub-population of DRG cells by resiniferatoxin [84]. Changes in voltage-dependent calcium currents have also been reported in guinea pig DRG cells [65]. (3) Acute conduction block Capsaicin application to the rat vagus nerve in vitro leads to a block of C-fibre conduction that initially parallels the depolarisation [58]. This initial phase of the conduction block probably arises from the accommodation of axons when they become depolarised. Application of high concentrations of capsaicin to cutaneous nerves in vivo blocks C-fibre conduction in rat, cat, ferret and monkey [4,13,66,67,73]. There are also smaller effects on A-fibres. In rabbit and guinea pig nerves capsaicin shows less acute blocking action, and the block appears relatively non-selective between A- and C-fibres [4]. At the single fibre level in the rat, 9 out of 10 C-PMN axons were blocked by 15 min exposure to 1% capsaicin whilst none out of 6 C-cold thermoreceptor axons were blocked [66].

Long-term reductions in numbers of C-fibre nociceptors in adult mammals (1) Immediate toxic reactions Brief exposure of C-fibre afferent terminals or axons to capsaicin produces reversible effects [58,76]. However, after exposure to higher concentrations, afferent C-fibres show long-lasting functional changes. For example exposure of rat peripheral nerve trunks to > 0.1 PM capsaicin for 15-30 min leads to block of C-fibre conduction lasting > 1-2 h [4]. Injection of high concentrations of capsaicin or analogs into skin also causes long-lasting loss of sensitivity in C-fibre poly-

63

modal nociceptor afferents (C-PMNs) [l&42,55]. During and mediately after exposure to capsaitin many C-afferent neurones show toxic reactions including axonal swelling (361 and swelling plus disruption of mitochondria and other organelles in nodose ganglion cell bodies [58]. In the nodose ganglion, partial protection is obtained if the ganglion is in a low calcium solution, indicating that influx of calcium may be partly responsible for the toxic changes. (2) Degeneration of C-afferent neurones following capsaicin treatment In neonatal rats and mice, systemic injection of capsaicin leads to large reductions in numbers of C-fibres and of DRG neuronal cell bodies [e.g., see reviews 11,18,31,60], with C-fibre numbers in rat peripheral nerves or spinal dorsal roots falling by m-95%. The fall is dose dependent and at high doses there is also a reduction in the number of small myelinated fibres [44,61]. Given the immediate toxic reactions of C-afferent neurones described above, degeneration of Cfibres would also be expected in adult rats. In fact, early studies with systemic capsaicin found no changes in C-fibre numbers in peripheral nerves or dorsal roots [14,41]. However, recent studies by Jancso et al. [36] have found a reduction in numbers of DRG cells by 17% and of saphenous nerve C-fibres by 48%. Adult systemic treatment also leads to marked reductions in C-fibre bundles in a number of visceral tissues, e.g., ureter [14,32] and in the respiratory tract [33]. Local application of capsaicin to peripheral nerves was also first reported not to lead to C-fibre loss [ l]. However, 1-4 days after local nerve treatment C-fibres have grossly abnormal appearance and their relation to Schwann cells is disrupted [25,34]. At 2-12 months after treatment 2 groups have now reported an approximate 40% loss of C-fibres [39,51,53,68]. Note that this indicates a rather poor ability of C-PMNs to regenerate following local&d exposure of axons to capsaicin. Despite the smaller numbers of C-fibres affected in adult rats, the behavioural changes in nociceptive reactions and the reductions in neurogenie inflammation are as great as after neonatal treatment [e.g., see 20,351. A possible reason for

this discrepancy is that the actions in the adult are more selective. Capsaicin affects all classes of Cafferent equally in neonatal rats, i.e., numbers of non-nociceptive C-fibres such as C-mechanoreceptors and cold thermoreceptors are reduced to the same extent as C-PMNs [50,83]. However, in adult rats non-nociceptive C-fibres appear to be unaffected [52,53,77]. In the rat saphenous nerve, 3-12 months after exposure to 1% capsaicin, the overall fall in C-fibre numbers is 40% but the fall in numbers of C-PMNs is 70-808 [53,68]. Thus the fall in C-PMN numbers is comparable after adult nerve treatment with the fall seen after neonatal treatment. Few studies of the long-term effects of capsaitin treatment have been performed on species other than the rat. In the guinea pig, systemic treatment leads to a permanent reduction in neuropeptide-contai~ng nerve terminals in a wide range of visceral tissues [63]. In the rabbit, treatment of the saphenous nerve with 1% capsaicin causes no loss of C-fibres 2 weeks later [54]. (3) Neuropeptide levels after capsaicin treatment and their relation to loss of C-fibes Much of the growth of interest in capsaicin in the late 1970s derived from the observation that levels of the neuropeptide substance P were greatly reduced by capsaicin treatment [40]. Capsaicin is, however, not selective for substance P and marked reductions in the levels of a number of other peptides (including calcitonin gene-related peptide (CGRP), somatostatin and vasoactive intestinal polypeptide (VIP)) have also been found [e.g., see 311. In general, levels of all peptides found in small afferent neurones supplying somatic and visceral tissues are reduced by capsaicin treatment. As stated by Holzer [31]: ‘It is to be expected that degenerative alterations in sensory neurons will have consequences for their contents of neuropeptides.’ In the rat, with all forms of capsaicin treatment, there appears to be significant longterm degeneration of C-fibre afferent neurones. Early data from rats treated as adults indicated no detectable degeneration but large reductions in substance P levels. This led to hopes that such treatment might produce a specific ne~~he~cal

effect, without causing any C-fibre degeneration. However, while this may be the case with low doses of capsaicin, it does not appear possible with the relatively high doses of capsaicin used in studies to date. Interestingly, in the rabbit following nerve treatment there is a 40% fall in substance P levels in the skin innervated by the treated nerve despite the absence of C-fibre degeneration

f541.

Therapeutic applications of capsaicin

An agent with capsaicin’s profile of actions, i.e., a selective desensitizing or toxic action on C-PMNs innervating the skin and on similar C-fibre afferents innervating other somatic and visceral tissues, has clear potential as a peripheral analgesic. It may also have anti-inflammato~ actions in diseases where there is a significant neurogenic inflammatory component. Systemic delivery of capsaicin is likely to cause problems due to the widespread loss of C-fibres. Rats treated systemically certainly show reduced nociceptive reactions. However, they also have reduced bladder emptying reflexes [56,57] and show diminished protective reflexes to inhaled irritants [48]. There are also indications that neuropeptides may play a part in tissue repair processes [26,62,64] and that survival of injured tissue may be reduced following systemic capsaicin treatment [43]. Local treatment of painful or inflamed regions or of the nerves supplying them is an alternative approach that avoids most of the potential problems with systemic capsaicin. Topical application is both the tra~tiona1 pharmaceutical use of capsaicin and the basis for recent therapeutic trials. Before describing the results of clinical use, I will first review what is known from experimental work in animals and man of capsaicin’s actions when applied directly to the skin. (2) Experimental studies of the effects of capsaicin treatment of the skin As already described, the topical application of capsaicin to the skin (or its injection into the skin) leads to excitation of C-PMN afferent terminals.

In man, application to the skin produces a burning pain sensation and/or a marked hyperalgesia to skin heating and pressure ~12,17,70,71]. After a single treatment, the hyperalgesia can last for up to 24 h [77]. Capsaicin also causes cutaneous vasodilatation, both at the application site and in the surrounding skin via an axon reflex flare. Repeat applications within 24 h lead to diminished effects, with pain reduced or absent and less vasodilatation. After several repeated applications the skin becomes completely insensitive to capsaicin. At this time axon reflex flare is absent, whether in response to skin heating [12], to electrical stimulation [69], to irritant chemical stimulation [2,9,22,29,78,79] or as part of an allergic response [49]. From about 24 h after starting treatment, the hyperalgesia can no longer be detected and, at least for skin heating, a period of hypalgesia occurs [12,38]. No changes are found in sensitivity to innocuous cooling or mechanical stimuli. Some diminution of warm sensitivity has been noted [38]. On stopping treatment, normal sensitivity and axon reflex flare return over 1 2 weeks. Repeated exposure of the oral mucosa to capsaicin also leads to desensitization to capsaicin’s irritant action, a phenomenon well known to those who eat ‘hot’ foods. Experimental studies [74] with repeated exposure of the tongue to 1% capsaicin found the expected reduction in sensitivity to capsaicin itself and to some other irritants (e.g., mustard oil). In addition, the difference Iimen for innocuous warming was significantly elevated. However, taste sensitivity was unchanged (again confirming the subjective impressions of hot food gourmets!). Thresholds for touch, pin-prick and pressure pain and difference limens for touch and innocuous cooling were also unchanged following capsaicin desensitization of the tongue [74]. Repeated topical application of capsaicin to feline or rodent skin produces desensitization of C-PMNs [23,42]. Intracutaneous injection of capsaicin or analogs also powerfully desensitizes rat [55] and monkey [15] C-PMNs and small subcutaneous injections in the rat elevate behavioural nociceptive thresholds for heat and pressure 2-~3 days later f75J. Antidromic vaso~latation~ a flare-

65

like response thought to be produced by C-PMNs [e.g., 471, is also depressed by capsaicin injections into rat skin and this takes 4 days to recover [55]. (3) Therapeutic ment

studies wing topical c~ps~~cin treut-

Considerable relief of post-herpetic pain has been reported in several recent studies [7,8,81]. Patients with long-standing localised pain applied a 0.025% or 0.075% capsaicin cream 4 times/day for several weeks. In the most recent double-band study [S] over half the patients using capsaicin obtained substantial pain relief compared with less than 10% with a ‘placebo’ cream. Further studies that are still in progress have been described by Bernstein [6] and apparently also show excellent results. Clearly these first results are very good, but need to be treated with the usual caution. With one exception, the longest duration of treatment mentioned in published reports is 6 weeks. The exception is a single case of oral postherpetic pain where complete relief had been achieved for 7 months [27]. A long-term study in a sizeable group of patients of the degree of continuing relief and of the effects of stopping applications of cream is clearly needed. It should also be noted that significant numbers of patients experience burning or stinging sensations initially with the capsaicin cream, so it must be very difficult to carry out a fully controlled, double-blind trial with this treatment. Nevertheless, these initial results are clearly very encouraging in a widespread condition that responds poorly to other pain relief strategies. The encouraging results with post-herpetic pain have stimulated trials of topical capsaicin treatment in other chronic pains of peripheral origin and limited spatial extent. An open label trial on 14 patients with pain following mastectomies has found significant levels of pain relief following a treatment comprising 4-6 weeks of 4 times daily application of 0.025% capsaicin cream to the painful area [82]. interestingly, in a number of these patients, as well as spontaneous pain from the affected region, they also felt unpleasant or painful sensations to light touch or pressure (hyperaesthesia, allodynia). These symptoms were also improved following capsaicin treatment. Unpub-

lished results from a double-blind trial of topical capsaicin treatment for painful diabetic neuropathy also indicate significant pain relief (Chad and Aronin, personal communication). Topical capsaicin app~cation has also been reported to relieve local tenderness in vulvar vestibulitis [24] and to be effective in reducing cold urticaria in sensitive patients [79]. However, relatively mild topical capsaicin treatment has been reported to enhance contact urticaria and allergic contact dermatitis 1801. What might be capsaicin’s mechanism of action in relieving these pathological conditions? Despite the large amount of experimental work with caps&in, this is actually quite a difficult question to answer. Most animal studies have used systemic treatment, application to nerve trunks, or injection into tissues. There are very few studies with topical application, and these have used 10 or more times higher concentrations than in the clinical trials. Experimental studies have indicated that capsaicin selectively excites and then desensitizes cutaneous C-fibres of the PMN type. The loss of axon reflex flare following topical application to human skin indicates that desensitization of Cfibres occurs also in man. The pain relief in man may therefore arise from a simple blockade of afferent input, i.e., a simple local anaesthetic-Ike action, but with only C-PMNs affected. A feature of the reports on peripheral pain treatment is that it takes from several days up to 1-2 weeks for relief to become apparent. The slow onset may be because the relatively low concentrations used take longer to act than the higher concentrations used in experimental studies. However, the situation could be more complex. It is now known that C-fibre inputs to spinal cord not only directly excite spinal neurones, but can also raise the overall level of spinal cord excitability 116,863. It is, therefore, possible that an important part of some chronic pain conditions is raised CNS excitability due to abnormal C-fibre inputs and that capsaicin is effective because it selectively reduces this activity. Procedures that affect all inputs (e.g., nerve section, local anaesthetics) may be less effective, perhaps because much of the transmission of nociceptive signals depends on the right balance between inputs, not just their pres-

ence or absence. This is, of course, an idea that was central to the gate control theory of Melzack and Wall [59]. It has been suggested that capsaicin acts largely by depleting substance P in C-fibres, both peripherally and centrally [6]. As discussed in the earlier sections of the review, capsaicin mostly appears to reduce substance P levels by causing C-fibre degeneration. In addition, capsaicin depletes many other neuropeptides, presumably again as a consequence of degeneration. Our preliminary work on rat skin shows that capsaicin treatment causes a depletion of substance P that outlasts the reduction in antidromic vasodilatation. There is also no evidence for a role of substance P in peripheral transduction of noxious stimuli. Substance P is only a very weak excitant of cutaneous afferents [19] and is not painful on application to cutaneous blister bases in man 1721.Topical capsaicin treatment appears unlikely to just deplete substance P and to leave other aspects of C-afferent terminal function intact and other neuropeptides unaffected. More information is clearly needed from experimental studies with topical capsaicin. Until that is available, it is probably best to keep an open mind on capsaicin’s exact mechanism of action when applied topically. (4) Other possible therapeutic uses of capsaicin The trials described in the previous section all use topical treatment, almost all for painful conditions. Another possible way in which capsaicin might be used would be to provide regional analgesia by treatment of nerve trunks. In the rat and monkey, exposure of cutaneous nerves to high concentrations of capsaicin causes long-term reduction in C-fibre numbers, particularly those involved in nociception. This might make nerve treatment with capsaicin a possible alternative to neurolytic blocking or surgical procedures for some pain conditions in man [37]. The nerves that are affected by capsaicin have a dual function. They signal about peripheral stimuli and they trigger local vascular changes (dilatation, increased permeability) by release of vasoactive peptides (e.g., as in axon reflex flare). There is growing evidence that these neuro-inflammatory actions of C-fibres may be important in some

disease states. The finding that cold urticaria is diminished by capsaicin treatment is an indication that desensitization of C-PMNs by capsaicin may be effective in treating some inflammatory conditions. An involvement of capsaicin-sensitive Cfibres has been proposed in arthritis [4.5,46], asthma [5] and a number of other conditions [see 561. If this involvement turns out to play a significant role in the pathology of these diseases, then capsaicin may have major therapeutic applications.

Summary

(1) In adult mammals capsaicin excites nociceptive C-afferents by a direct membrane action involving the opening of channels permeable to sodium, calcium and other cations. (2) Direct application of high concentrations of capsaicin to sensory neurones for 30 min or less can trigger degenerative changes leading to permanent loss of most nociceptive C-fibres and a consequent reduction in levels of neuropeptides such as substance P in innervated tissues and in afferent termination zones in the CNS. (3) Initial topical applications of capsaicin to skin cause C-fibre excitation and pain. Repeated application causes nociceptor desensitization in rodent skin and hypalgesia in human skin. Axon reflex flare, an ‘effector’ action of afferent C-fibres, is also diminished or abolished. (4) Limited trials in localised chronic pain conditions in man, notably post-hetpetic neuralgia, have shown that topical capsaicin treatment over several weeks can give useful pain relief. (5) Capsaicin may have further applications in pain relief and in inflammatory diseases that have a significant neuro-inflammatory component.

References 1 Ainsworth, A., Hall, P., Wall, P.D., Allt, G., Mackenzie, M.L., Gibson, S. and Polak, J.M., Effects of capsaicin applied locally to adult peripheral nerve. II. Anatomy and enzyme and peptide chemistry of peripheral nerve and spinal cord, Pain, 11 (1981) 379-388.

67

6 7

8

9

10

11

12

13

14

15

16

17

18

Anand, P., Bloom, S.R. and McGregor, G.P., Topical caps&in pretreatment inhibits axon reflex vasodilatation caused by somatostatin and vasoactive intestinal polypeptide in human skin, Br. J. Pharmacol., 78 (1983) 665669. Baccaglini, PI. and Hogan, P.G., Some rat sensory neurons in culture express characteristics of differentiated pain sensory cells, Proc. Nat. Acad. Sci. (U.S.A.), 80 (1983) 594-598. Baranowski, R., Lynn, B. and Pini, A., The effects of locally applied capsaicin on conduction in cutaneous nerves in four mammalian species, Br. J. Pharmacol., 89 (1986) 267-276. Barnes, P.J., Asthma as an axon reflex, Lancet, i (1986) 242-244. Bernstein, J.E., Capsaicin in postherpetic neuralgia, Med. Times, 117 (1989) 113-116. Bernstein, J.E., Bickers, D.R., Dahl, M.V. and Roshal, J.Y., Treatment of chronic postherpetic neuralgia with topical capsaicin, J. Am. Acad. Dermatol., 17 (1987) 93-96. Bernstein, J.E., Korman, N.J., Bickers, D.R., Dahl, M.V. and Lawrence, L.E., Topical capsaicin treatment of chronic postherpetic neuralgia, J. Am. Acad. Dermatol., 21 (1989) 265-270. Bernstein, J.E., Swift, R.M., Soltani, K. and Lorincz, A.L., Inhibition of axon reflex vasodilatation by topically applied capsaicin, J. Invest. Dermatol., 76 (1981) 394-395. Bevan, S. and Forbes, A., Membrane effects of capsaicin on rat dorsal root ganglion neurones in cell culture, J. Physiol. (Lond.), 398 (1988) 28P. Buck, S.H. and Burks, T.F., The neuropharmacology of capsaicin: review of some recent observations, Pharmacol. Rev., 38 (1986) 179-226. Carpenter, S.E. and Lynn, B., Vascular and sensory responses of human skin to mild injury after topical treatment with capsaicin, Br. J. Pharmacol., 73 (1981) 755-758. Chung, J.M., Lee, K.H., Hori, Y. and Willis, W.D., Effects of capsaicin applied to a peripheral nerve on the responses of primate spinothalamic tract cells, Brain Res., 329 (1985) 27-38. Chung, K., Schwen, R.J. and Coggeshall, R.E., Uretral axon damage following subcutaneous administration of caps&in in adult rats, Neurosci. Lett., 53 (1985) 221-226. Cohen, R.H., Campbell, J.N., Khan, A.A. and Meyer, R.A., The deactivation of C-fiber nociccptive receptors following intradermal injection of the capsaicin analogue NE-21610, Sot. Neurosci. Abst., 14 (1988) 912. Cook, A.J., Woolf, C.J., Wall, P.D. and McMahon, S.B., Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input, Nature, 325 (1987) 151-153. Culp, W.J., Ochoa, J., Chne, M. and Dotson, R., Heat and mechanical hyperalgesia induced by capsaicin. Cross modality threshold modulation in human C nociceptors, Brain, 112 (1989) 1317-1331. Fitzgerald, M., Capsaicin and sensory neurones - a review, Pain, 15 (1983) 109-130.

M. and Lynn, B., The weak excitation of some 19 Fitzgerald, cutaneous receptors in cats and rabbits by synthetic substance P, J. Physiol. (Lond.), 293 (1979) 66P-67P. M. and Woolf, C.J., The time course and 20 Fitzgerald, specificity of the changes in the behavioural and dorsal horn cell responses to noxious stimuli following peripheral nerve capsaicin treatment in the rat, Neuroscience, 7 (1982) 2051-2056. 21 Forbes, C.A. and Bevan, S., Single channels activated by capsaicin in patches of membrane from adult rat sensory neurones in culture, Neurosci. Lett., Suppl. 32 (1988) S3. 22 Foreman, J.C., Jordan, C.C., Oehme, P. and Renner, H., Structure-function relationships for some substance P-related peptides that cause wheal and flare reactions in human skin, J. Physiol. (Lond.), 335 (1983) 449-465. 23 Foster, R.W. and Ramage, A.G., The action of some chemical irritants on somatosensory receptors of the cat, Neuropharmacology, 20 (1981) 191-198. 24 Friedrich, E.G., Therapeutic studies on vulvar vestibulitis, J. Reprod. Med., 33 (1988) 514-518. 25 Handwerker, H.O., Holzer-Petsche, U., Heym, C. and Welk, E., C-fibre functions after topical application of capsaicin to a peripheral nerve and after neonatal capsaicin treatment. In: L.A. Chahl, J. Szolcsanyi and F. Lembeck (Eds.), Antidromic Vasodilatation and Neurogenic Inflammation, Akademiai Kiadh, Budapest, 1984, pp. 57-78. 26 Hanley, M., Neuropeptides as mitogens, Nature, 315 (1985) 14-15. 27 Hawk, R.J. and Millikan, L.E., Treatment of oral postherpetic neuralgia with topical capsaicin, Int. J. Dermatol., 27 (1988) 336. 28 Hayes, A.G., Hawcock, A.B. and Hill, R.G., The depolarising action of capsaicin on rat isolated sciatic nerve, Life Sci., 35 (1984) 1561-1568. 29 Helme, R.D. and McKeman, S., Flare responses in man following topical application of capsaicin. In: L.A. Chahl, J. Szolcsanyi and F. Lembeck (Eds.), Antidromic Vasodilatation and Neurogenic Inflammation, Akademiai Kiadb, Budapest, 1984, pp. 303-312. 30 Heyman, I. and Rang, H.P., Depolarizing responses to capsaicin in a sub-population of rat dorsal root ganglion cells, Neurosci. Lett., 56 (1985) 69-75. 31 Holzer, P., Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides, Neuroscience, 24 (1988) 739-768. 32 Hoyes, A.D. and Barber, P., Degeneration of axons in the ureteric and duodenal nerve plexuses of the adult rat following in vivo treatment with capsaicin, Neurosci. Lett., 25 (1981) 19-24. 33 Hoyes, A.D., Barber, P. and Jagessar, H., Effect of capsaitin on the intraperitoneal axons of the rat trachea, Neurosci. Lett., 26 (1981) 329-334. 34 Jancso, G., Ferencsik, M., Such, G., Kiraly, E. and Nagy, A., Morphological effects of capsaicin and its analogues in newborn and adult mammals. In: R. Hakanson and F.

6X

35

36

37 38

39

40

41

42 43

44

45

46

47

48

49

50

51

Sundler (Eds.), Tachykinin Antagonists. Elsevier, Amsterdam. 1985, pp. 35-44. Jancso, G.. Kiraly. E. and Jancso-Gabor, A.. Direct evidence for an axonal site of action of capsaicin, Arch. Pharmacol., 313 (1980) 91-94. Jancso. G., Kiraly, E.. Joo, F., Such. G. and Nagy. A., Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat. Neurosci. Lett., 59 (1985) 209-214. Jancso, 0. and Lynn. B., Possible use of capsaicin in pain therapy, Clin. J. Pain. 3 (1987) 123-126. Jancso, G., Obal, F., Toth-Kasa. I., Katona. M. and Husz, S.. The modulation of cutaneous inflammatory reactions by peptide-containing sensory nerves. Int. J. Tissue Reactions. 7 (1985) 449.-457. Jancso, G.. Such. G. and Rodel. C., A new approach to selective regional analgesia. In: F. Sicuteri et al. (Eds.). Trends in Cluster Headache, Elsevier. Amsterdam, 1987. pp. 59-68. Jessell. T.M.. Iversen, L.L. and Cuello. A.C., Capsaicin-induced depletion of substance P from primary sensory neurones, Brain Res., 152 (1978) 183-188. Joo, F., Szolcsanyi. J. and Jancso-Gabor, A., M~t~hondrial alterations in the spinal ganglion cells of the rat accompanying the long-lasting sensory disturbance induced by capsaicin. Life Sci., 8 (1969) 621-626. Kenins. P.. Responses of single nerve fibres to capsaicm applied to the skin, Neurosci. Lett., 29 (1982) X3-88. KJartansson, J.. Dalsgaard, C.-J. and Jonsson, C.-E.. Decreased survival of expe~mental critical flaps in rats after sensory denervation with capsaicin. Plast. Reconstruct. Surg.. 79 (1987) 218-221. Lawson. S.N. and Nickels, SM., The use of morphometric techniques to analyse the effect of neonatal capsaicin treatment on dorsal root ganglia and dorsal roots. J. Physiol. (Land.). 303 (1980) 12P. Levine. J.D., Coderre, T.J. and Basbaum, A.I., The petiphera1 nervous system and the inflammatory process. In: R. Dubner, G.F. Gebhart and M.R. Bond (Eds.), Proc 5th Int. Congress on Pain, Elsevier, Amsterdam. 1988. pp. 33-43. Levine, J.D., Moskowitz, M.A. and Basbaum, A.I., The contribution of neurogenic inflammation in experimental arthritis, J. Immunol., 135 (1985) 843s-8475. Lisney. S.J.W. and Bharali, L.A.M., The axon reflex: an outdated idea or a valid hypothesis. News Physiol. Sci.. 4 (1989) 45-48. Lundberg, J.M. and Saria. A.. Capsaicin-induced desensitiLation of airway mucosa to cigarette smoke, mechanical and chemical irritants, Nature, 302 (1983) 251-253. Lundblad, L., Lundberg, J.M.. Anggard. A. and Zetterstrom, 0.. Caps&in-sensitive nerves and the cutaneous allergy reaction in man, Allergy, 42 (1987) 20-25. Lynn, B.. Effect of neonatal treatment with capsaicin on the numbers and properties of cutaneous afferent units from the hairy skin of the rat, Brain Res.. 322 (1984) 255-260. I.ynn. B.. The immediate and long-term effects of applying

52

53

54

55

56

57

5X

59 60

61

62

63

64 65

66

capsaicin to cutaneous nerves. Acta Physiol. Hung., 69 (1986) 287-294. Lynn, B.. Carpenter, SE. and Pini, A., C’apaaicin and cutaneous afferents. In: L.A. Chahl, J. Szolcsanyi and F Lembeck (Eds.). Antidromic Vasodilatation and Neurogenie Inflammation. Akademiai Kiadh. Budapest. 1984, pp. 83-92. Lynn. B., Pini. A. and Baranowski. R., Injury of somatosensory afferents by capsaicin: selectivity and failure to regenerate. In: L.M. Pubols and B.J. Se&e (Ed%), Effects of Injury on Trigeminal and Spinal Somatosensory Syhterns. Alan R. Liss, New York. 1987, pp. 115-124. Lynn, B. and Shakhanbeh, J.. Substance P content of the skin, neurogenic inflammation and numbers of C-fihres following capsaicin application to a cutaneous nerve in the rabbit, Neuroscience, 24 (I 988) 769-775. Lvnn. B. and Ye, W.. I~es~sitization of C-fibres of the polymodal nociceptor type (C-PMNs) by intradermal injection of capsaicinoids. In: Proc. XXX1 Int. Congress of Physiol. Sci., Helsinki. 1989, abst. P2496. Ma&, C.A. and Meli. A.. The sensory-efferent function of capsaicin-sensitive sensory neurons, Gen. Pharmacol.. 19 ( 1988) l-43. Maggi, C.A., Santicioli. P.. Borsim, F., Guiliani. S. and Meli, A., The role of capsaicin-sensitive innervation in the rat urinary bladder in the activation of micturitlon reflex. N.-S. Arch. Pharmacol., 332 (1986) 276-283. Marsh. S.J., Stansfeld, C.E., Brown. D.A., Davey, K. and McCarthy, D.. The mechanism of action of capsaicin on sensory C-type neurons and their axons in vitro, Neuroscience. 23 (1987) 215 -289. Melzack, R. and Wall, P.D.. Pain mechanisms: a nru theory. Science, 150 (1965) 971-979. Nagy. J.I.. Capsaicin: a chemical probe for sensory neuron mechanisms. In: L..L. Iversen, SD. Iversen and S.H. Snyder ( Eds.). New Techniques in Psychopharmacology. Handbook of Psychopharma~(~logy, Vol. 15. Plenum, New York. 1982. pp. 185-235. Nagy. J.I.. Iversen, L.L., Goedert. M., Chapman. D. and Hunt, S.P., Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat, J. Neuroscl.. 3 (1983) 399-406. Nilsson, J.. von Euler. A.M. and Dalsgaard, C.-J., Stimulation of connective tissue ceil growth by substance P and substance K, Nature. 315 (1985) 61-63. Papka. R.E., Furness, J.B., Della. N.G., Murphy, R. and Costa. M.. Time course of effect of capsaicin on ultrastructure and histochemistry of substance P-immunoreactive nerves associated with the cardiovascular system. Neuroscience. 12 (1984) 1277-1292. Payan, D.G., McGillis. J.P. and Goetzl, E.J.. Neuroimmunology, Adv. Immunol., 39 (1986) 299-323. Petersen, M., Wagner, G. and Pierau, F.-K., Modulation of calcium-currents by capsaicin in a subpopulation of sensory neurones of guinea pig, Naunyn-Schmiedeberg’s .Arch. Pharmacol.. 339 (1989) 184-191. Petsche. (1.. Fleischer, E., Lembeck. F. and Handwerker.

69

67 68

69

70

71

72

73

74

75

76

H.O., The effect of capsaicin application to a peripheral nerve on impulse conduction in functionally identified afferent nerve fibres, Brain Res., 265 (1983) 233-240. Pini, A., Effects of capsaicin on conduction in a cutaneous nerve of the rat, J. Physiol. (Lond.), 338 (1983) 6OP-61P. Pini, A., Baranowski, R. and Lynn, B., Long-term reduction in the number of C-fibre nociceptors following capsaicin treatment of a cutaneous nerve in adult rats, Eur. J. Neurosci., 2 (1990) 89-97. Roberts, R.G.D., Westerman, R.A., Widdop, R.E., Kotzman, R.R. and Carter, B., Effects of capsaicin on cutaneous axon reflex vasodilatation in man, Proc. Aust. Physiol. Pharmacol. Sot., 18 (1987) 95P. Simone, D.A., Baumann, T.K. and LaMotte, R.H., Dosedependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin, Pain, 38 (1989) 99-107. Simone, D.A., Ngeow, J.Y., Putterman, G.J. and LaMotte, R.H., Hyperalgesia to heat after intradermal injection of capsaicin, Brain Res., 418 (1987) 201-203. Stewart, J.M., Getto, C.J., Neldner, K., Reeve, E.B., Kirvoy, W.A. and Zimmermamr, E., Substance P and analgesia, Nature, 262 (1976) 784-785. Such, G. and Jancso, G., Axonal effects of capsaicin: an electrophysiological study, Acta Physiol. Hung., 67 (1986) 53-63. Szolcsanyi, J., A pharmacological approach to elucidation of the role of different nerve fibres and receptor endings in mediation of pain, J. Physiol. (Paris), 73 (1977) 251-259. Szolcsanyi, J., Sensory receptors and the antinociceptive effects of capsaicin. In: R. Hakanson and F. Sundler (Eds.), Tachykinin Antagonists, Elsevier, Amsterdam, 1985, pp. 45-54. Szolcsanyi, J., Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and

ultra-violet radiation, J. Physiol. (Lond.), 388 (1987) 9-23. 77 Szolcsanyi, J., Anton, F., Reeh, P.W. and Handwerker, H.O., Selective excitation by capsaicin of mechano-heat sensitive nociceptors in rat skin, Brain Res., 446 (1988) 262-268. 78 Toth-Kasa, I., Jancso, G., Bognar, A., Husz, S. and Obal, F., Capsaicin prevents histamine-induced itching, Int. J. Clin. Pharm. Res., 6 (1986) 163-169. 79 Toth-Kasa, I., Katona, M., Obal, F. et al., Pathological reactions of human skin: involvement of sensory nerves. In: L.A. Chahl, J. Szolcsanyi and F. Lembeck (Eds.), Antidromic Vasodilatation and Neurogenic Inflammation, Akademiai Kiado, Budapest, 1984, pp. 317-328. 80 Wallengren, J. and Moller, H., The effect of capsaicin on some experimental inflammations in the human skin, Acta Dermato-Vener., 66 (1986) 375-380. 81 Watson, C.P.N., Evans, R.J. and Watt, V.R., Post-herpetic neuralgia and topical capsaicin, Pain, 33 (1988) 333-340. 82 Watson, C.P.N., Evans, R.J. and Watt, V.R., The postmastectomy pain syndrome and the effect of topical capsaicin, Pain, 38 (1989) 177-186. 83 Welk, E., Fleischer, E., Petsche, U. and Handwerker, H.O., Afferent C-fibres in rats after neonatal capsaicin treatment, Pfliiger’s Arch., 400 (1984) 66-71. 84 Winter, J., Dray, A., Wood, J.N., Yeats, J.C. and Bevan, S., Resiniferatoxin - a potent capsaicin-like sensory neurone excitotoxin, Brain Res., in press. 85 Wood, J.N., Winter, J., James, I.F., Rang, H.P., Yeats, J. and Bevan, S., Capsaicin-induced ion fluxes in dorsal root ganglion cells in culture, J. Neurosci., 8 (1988) 3207-3220. 86 Woolf, C.J. and Wall, P.D., The relative effectiveness of C primary afferent fibres of different origins in evoking a prolonged facilitation of the flexor reflex in the cat, J. Neurosci., 6 (1986) 1433-1442.