TipS - May 2990 IVul. 211

185

Dopamine LIJreceptor antagonists and schizophrenia In the report of a recent symposium on schizophrenia (TPS, February 1990)‘, it was stated that ‘Schering’s selective D7 a~#agonist SCH233%? is now in clinical trial’. Unfortunately, this is not the case. SCH23390 was never developed &nically because of its unacceptably short duration in non-human primates (most notably Rhesus monkeys). Indeed, SCH23390 has not even been toxicologically evaluated for potential clinical use. Thus, SCH23390 has not been nor is it expected to be clinically developed by Schering. By contrast, SCH39166 - Schering’s new selective dopamine Dr receptor antagonis? - differs from

SCH23390 butes:

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e SCH39166 is from a different chemical class (benzonaphthazepine) than SC)123390 (benzazepinel”. e SCH39l66 is more selective for Dr receptors than is SCH23340, particularly versus the 5-HT2 receptora. 0 SCH39166 has an acceptably long duration in the non-human primate2. 6 SCH39166 has been evaluated in three-month rodent and nonhuman primate toxicity tests. No limiting effects were observed. In all other pharmacological tests -

Modulation of neuro infiammatio~: novel to inflammato~ disease Peter J. Barnes, Maria G. Betvisi and Duncan F. Rogers Neurugeni~ ~n~~mrna~~un~ which inuofvesthe release of net~~pep~idgs from ~apsa~cii~-sensitive sensory fmves, may conf~*b~te to i~f~a~~ato~ &seam of fhe a&ways, joints, bladder, skin, eye and gut. Peter Barnes and colleagues review serne of the therapeutic strategies that can be used to inhibif this neu~o~en~~i~~~am~ation~with part~~~l~~referents to the res~~rafor~ tract. There is a close interrelationship between in~ammation and neural suntrol, In~ammato~ mediators may facilitate or modulate the release of neurotransmitters through P. I. Barnes is Professor of Thorncic Medicine, M. G. Beluisi is a Researck Fe&no and D. F. Rogers a Lecturer in the Dqartatent 5f Thwacic Medicine, ~a~~oaa~Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK.

prejunctional receptors and, conversely, neural mechanisms themselves may contribute to the inflammatory reaction. There are indications that chronic inflammation may lead to changes in the transcription and post-translational processing of peptide neurotransmitters~ and even to long-term structural changes in innervation.

including those predictive of clinical antipsychotic efficacy the behaviors of !%I-@3390 and SCN39l66 are identical Because of this profile, SCH39166 is being progressed clinically. However, the length and compkity of trials in schizophrenia mean that an unequivocal answer on the efficacy of dopamine D, receptor antagonists may be a few years away. Rrcn~4v E. CHIPKIN Schering-Plozcglr Researck, MM) Gallopittg Hill Road, Keniitoorth, Nj 07033, USA.

References 1 Abbott, A. (1990) Trends Pkwmcoi. Sri. 11,&I-51 2 Chipkin, R. E. et IL!.(1988) 1. Pbarmacal. 247,109~1102 3 Betger, 1. G. E: at. (1989) f. Med. Ckem. 32, 1913-1921 4 McQuade, R. D., D&y, R. A., Anderson, C. C., Chipkin, R. E. and Bamett, A. (1989) FASEB 1.4, A601

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SCH39166: trms-(-)+as, 13bR)-‘ll-chloro6ba,7~,9,13b-hexahydm-7-meth~l-5Nbenzo/d/-naphth[2,1-bjazepin-12-01

The classical investigations of Bruce in the early part of this century suggested that local vascular changes could result from retrograde activation of sensory nerves to the skin, and he introduced the concept of the axon refIex and neurogenic inflammation’. Later workers failed to confirm the involvement of neural mechanisms in inflammation, and interest in neurogenic inflammation waned until Jams& Szolcsdnyi and colleagues demonstrated, in the 196Os, that antidromic stimulation of sensory nerves induced an inflammatory response in the skin. After failing to block it with a range of antagonists, they postulated that this response was due to release of a ‘neurohumour’ which was not acetyl~holine, histamine, !%HT, adrenaline or noradrenaline2. The abolished, was inflammation however, by denervation and by pretreatment with capsaicin, the pungent extract of hot peppers of the Capsicunz family, which depletes a population of chemosensitive primary afferent C fibres of their peptide neurotransmitters. IvIostattention concerning neurogenie infl~mat~on has focused on capsaicin-sensitive primary

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Fe. 1, lnh~i~ by @ids of sc-nsory ne~~~iat~ responses. Lett: in spinal cord, releasefmm spfnat a&we&is i~~~~~byenkephafi (Wk. substam P (SP, m&sad from inhibitoryintameumns and achingvia p-opioid recepfors. [RRer Jesse& T. M.and lversen. L. L. (19771 Natura 268, 549-551, and Yaksh, T. L. et at. (1980) Nature 266, 155-l 57.1 Right: similar inhibitory q&id receptors may be present on the ~@heml ends of sensory nerves and thus prevent the features of neumgenic infkvnmation, such as microvascular leakage (ML), vasodilatation (VD), muchis and f&k-t sacretion (MS) and smooth muscle contracfion (WC) (as h bronchi and gut).

sensory neurons that can release transmitters from their peripheral endings, thereby having an ‘efferent’ or, more accurately, a local effector function”. The neurotransmitters involved are thought to be neuropeptides, including the tachykinins substance I’, neurokinin A and eledoisin-like peptide, and calcitonin gene-related peptide (CGRP). Together, these peptides produce inflammatory effects such as vasodilatation, plasma exudation, mucus secretion, inflammatory cell recruitment and activation and, in certain sites, smooth muscle contraction. Other neuropeptides, such as somatostatin, vasoactive intestinal polypeptide, galanin and corticotropin-releasing factor, have also been described in various capsaicin-sensitive sensory nerves. Reiease of muitipie pepiides provides the potential for synergistic interactions; for example, the vasodilator action of CGRP may potentiate plasma exudation induced by substance P in the skin, presumably by increasing bloodflow to the site of leakage. Conversely, CGlW may act as a functional an~gonist to neuro-

kinin A in certain situations. inflammation has Neurogenic been demonstrated in many organs, including skin, respiratory tract, eye, alimentary tract, joints and bladder (for review see Refs 4 and 5). Polymodal nociceptors may be stimulated by a variety of agents, including inflammatory mediators (such as histamine, prostaglandins and bradykinin) and selectively by capsaicin. Neurogenic inflammatory responses presumably evolved as part of our natural defence system and the inflammatory response to injury is likely to be involved in tissue repair. However, neurogenie mechanisms may con~bute to the inflammation component of a number of diseases, including asthmae, rhinitis7, arthritiss, conjunctivitis4,5, ulceration of the alimentary tract and skin inflammatiorF. k4uch of the evidence neurogenic for inflammatory mechanisms is derived from studies in rodents, in which capsaicin-sensitive nerves are prominent. However, in humans, these nerves are also involved in the skin, where desensitization by repeated application of topical

capsaicin reduces responses to allergens in atopic subjects’, and in the nose, where capsaicin desensitization ameliorates vasomotor rhinitis*O. It follows that strategies to reduce neurogenic inflammation may be a useful new therapeutic approach to inflammatory diseases. There is now considerable interest in the development of such drugs, which might have therapeutic application in a wide range of inflammatory diseases. This review focuses on drug strategies aimed at reducing the pathophysiological manifestations of neurogenic inflammation by inhibiting sensory nerve function, with particular reference to the respiratory tract. Receptor antagonists ~chykinin receptor Severai antagonists have been developed that are peptide analogues. Many of these lack specificity, are weakly active, may have partial agonist effects or may be rapidly degraded, making them unsuitable for clinical development. Even relatively potent and stable antagonists suffer from the disadvantages of peptides as drugs because of difficulty in delivery to the target site. No non-peptide antagonists for sensory neuropeptides are currently available, although the development of such drugs in the future seems Iikely. However, even effective neuropeptide receptor antagonists may not be useful, since sensory nerves release multiple peptides, each of which may induce a different physiological response by interacting with specific receptors. Thus, blocking a single receptor, e.g. an NK1 receptor, will not prevent effects mediated through other receptors such as NK2 or CGRP receptors (or even through receptors for neuropeptides that have not yet been dispotent covered). Nevertheless, and selective antagonists may be useful in elucidating the role of sensoF1I --~=VPS - in disease, and in diseases in which the effects of a particular sensory neuropeptide predominate. It should be remembered, however, that tachykinins exist in the CNS and in nerves (e.g. in gut) that are not capsaicin-sensitive, so NK receptor antagonists may have effec~.~yond ~ibition of neurogenic in~ammation.

TiPS - May 1990 [Vol. 121 Prejunctional inhibition Inhibition of release of neuropeptides from sensory nerve endings may be a more useful approach in controlling neurogenie inflammation; several agonists act on prejunctional inhibitory receptors on sensory nerves.

Opioids The inhibitory

prejunctional effects of opioids on both central and peripheral sensory nerves have been widely studied. Opiate analgesics inhibit the evoked release of substance P from the trigeminal nucleus in vitro and from the spinal cord in z&o by an action on inhibitory opioid receptors located on the central terminals of primary afferent neurons. Enkephalins may be considered to be the endogenous inhibitors of substance-P-containing neurons and it is not surprising that the peripheral ends of these ireurons also have inhibitory opioid receptors (Fig. 1). Both morphine and a number of synthetic enkephalin analogues inhibit the plasma extravasation in the rat paw induced by antidromic stimulation of the saphenous nerve, and the response is reversed by the opioid receptor antagonist naloxone*l. Opioids also inhibit the release of substance P from intramural neurons in guinea-pig ileum in a nalmanner12. In oxone-reversible guinea-pig bronchi in vitro the non-cholinergic bronchoconstrictor response to electrical field stimulation, which is due to release of tachykinins from sensory nerves, is inhibited by morphine in a dose-dependent manner and is reversed by naloxone*3. Since morphine has no effect on comparable bronchoconstriction induced by substance P, this would suggest that morphine must be inhibiting the release of tachykinins. A similar inhibitory effect on non-cholinergic bronchoconstriction is observed in guineapigs in viva 14. This effect is mediated by y-opioid receptors, since the y-selective agonist DAMGO is capable of completely suppressing the bronchoconstrictor response to antidromic nerve stimulation, whereas a b-selective agonist is less c-ffective, and a K-selective agonist ineffective13J4. Opioids also inhibit neurogenic plasma extravasation in guinea-

187 pig airways, which is induced by vagus nerve stimulation in the presence of atropine, at doses that are ineffective against substanceP-induced leak15 (Fig. 2). Substance P stimulates mucus secretion from human bronchi in vitro, and this is mimicked by capsaicin16. Morphine inhibits the secretory response to capsaicin, implying that inhibitory opioid receptors are also present on sensory nerves in human airways. Whether endogenous opioids (enkephalins) have a role in regulating the release of neuropeptides from the peripheral ends of sensory nerves is not certain. Enkephalinlike immunoreactive nerves are found in the alimentary and respiratory systems. However, naloxone alone does not enhance either neurogenic plasma leakage15 or non-cholinergic bronchoconstriction induced by vagus nerve stimulation14, which argues against an inhibitory role for endogenous opioids under normal experimental conditions. However, it is possible that the actions of endogenous opioids only become apparent under certain pathoconditions. For physiological example, in experimental cholecystitis in cats, exogenous opiates inhibit the increased fluid secretion via a modulatory action on nerves17. Naloxone alone increases fluid secretion only in the inflamed

gall bladder and is without effect in the normal gall bladder, indicating that endogenous opioids may only play a modulatory ro!e in the setting of chronic inflammation. Whether similar modulatory mechanisms are enhanced in human inflammatory disease remains to be elucidated. Opiates might, therefore, have a therapeutic role in inhibiting neurogenie inflammation by a peripheral aciion. To avoid problems of stimulation of central opioid receptors and dependency, peripherally acting opioids that do not penetrate the brain have been developed. For example, the pentapeptide opioid BW443C inhibits the bronchial hyperreactivity that follows ozone exposure in anaesthetized cats18. Whether this class of drug will be useful in the therapy of asthma or in other chronic inflammatory conditions remains to be determined.

Other agonists Several other agonists have recently been found to inhibit release of sensory neuropeptides (Fig. 3). Noradrenaline exerts an antinociceptive effect by inhibiting neuropeptide release from primary afferents in the CNS, yet in adrenergic the periphery nerves appear to facilitate neurogenie inflammation4,s. The effects

Fig. 2. Effects of morphine on plasma exudation. a: Inhibition by morphine of extravasation measured by extravasation of Evans blue dye in guinea-pig bronchr induced by stimulation of the vagus nerve (in the presence of atropine to block chotinergic effects). This inhibition was reversed by naloxone, indicating that opioid receptors are involved. b: Morphine has no effecton the equivalent amount of leakage induced by i.v. substance P (SP), indicating that opioid receptors inhibit the release of neuropeptides from sensory nerves. (Adapted from Ref. 15.)

TiPS - Mny 1990 IVoi. 211

Fg. 3. Inhibitionof neumgenic inflammatory effects can be achievedby inhibiting activation of sensory neurons, by activating prejunctionaf receptors that inhibit neumpeptide release, or by blockade of sensory neuropeptide receptors. K +channel activatorsmimic the effects of agonists at presynaptic receptors.

of adrenergic stimulation are cona2-adrenoceptor flicting, since agonists are effective both in vivo’q and in vit&O in inhibiting non-cholinergic neural bronchoconstriction m guinea-pigs. Neuropeptide Y (NPY), a co-transmitter in adrenergic nerves, also inhibits this neural response in guinea-pig airways, both in vitro20.21 and in viuo*‘, and inhibits the contractile responses produced by activation of capsaicin-sensitive primary afferents in the guinea-pig isolated left atria=, indicating that adrenergic nerves may inhibit sensory neuropeptide release, both via noradrenahne acting through cu-adrenoceptors and by NPY. The central inhibitory neurotransmitter, GABA is increasingly recognized to exist in peripheral nerves; it inhibits non-cholinergic neural bronchoconstriction in guinea-pigs”. This effect is mediated via GABAs receptors, since the GABAs receptor agonist baclofen is effective, whereas a GABAA receptor agonist is not.

Another neuropeptide, Falanin, noninhibits non-adrenergic cholinergic neural bronchoconstriction in guinea-pig airways in Citroen. Somatostatin inhibits release of substance-P-like immunoreactivity and consequent vasodilatation in cat dental pulp in response to nerve stimulation25 and inhibits neurogenic vasodilatation and plasma extravasation in the rat foot padz6; it is, however, ineffective on non-cholinergic bronchocons~ctor nerves in airways (D. Stretton and P. Barnes, unpublished}, suggesting that prejunctional receptors on sensory nerves may vary at different sites. Corticotropin-releasing factor (CRF) appears to be co-localized with substance P, somatostatin and [Leulenkephalin in dorsal root and trigeminal ganglion of the rat and is depleted by capsaicin pretreatment. CRF inhibits neurogenic plasma leakage in the rat foot pad27 and trachea28 by a specific receptor-mediated mechanism not related to secondary

release of enkephalins. Interestingly, a CRF antagonist alone increases plasma leakage, indicating a functional inhibitory role for endogenous CRF, whereas naloxone is ineffective. Structurally related peptides of the corticoliberin superfamily, which includes sauvagine and urotensin I, are even more potent; all inhibit the inflammatory response to noxious and thermal stimuliz7. Histamine is an inflammatory mediator with a number of effects, including plasma exudation, airway smooth muscle contraction and sensory nerve activation (mediated via Hi receptors) and vasodilatation (via Hi and HZ receptors). A third type of histamine receptor (Hs) has recently been identified in both central and peripheral nerves, where it appears to mediate inhibitory effects. In guinea-pig airways an H3 receptor agonist, R-&methylinhibits both nonhistamine. cholinergic neural bronchoconstriction and neurogenic plasma exudationsa. These effects are completely reversed by the selective I-IS antagonist thioperamide. Since mast cells and sensory nerves are often c!osely associated it is possible that basal histamine leakage from mast cells prevents activation of sensory nerves via Hs receptors, whereas the massive release that may occur with degranulation after allergen overrides this effect and acts on Hr and Ha receptors on target cells.

A common mechanism? The presence of so many inhibitory prejunctional receptors on sensory ner:es suggests that there may be a common mode of action. Electrophysiologica! studies have demonstrated that several of the agonists that have inhibitory actions on sensory nerves are al50 inhibitor in central neurons by opening a common channel, leading to hyperpolarization31. The multiple prejunctional receptors on sensory nerves may also open a common K+ channel and this is supported by the fact that the K+ channel activator, cromakalim (BRL34915), is effective in inhibiting non-cholinergic neural bronchoconstriction in guinea-pig airwayssz. The inhibitory effects of cromakalim are reduced by the K+ channel biocker, glibenclamide, indicating that an ATP-

TiPS - May 1990 iVo1. 111 sensitive K+ channel may be involved3*. Whether glibenclamide also blocks the prejunctional Inhibitory effects of opioids and other agents is not yet certain, however.

Sensory nerve blockade Local anaesthetics, such as lignocaine, inhibit the neurogenic flare in skin2a3. However, effective topical anaesthesia is difficult to achieve at other sites, such as the airways. In addition, anaesthesia is probably not a aseful therapeutic option since it also inhibits other afferent fibres. This may be hazardous in the airways if anaesthesia is sufficient to inhibit the defensive cough reflex. Capsaicin at low doses acutely activates sensory nerves and releases sensory neuropeptides, but high-dose administration leads to depletion of these peptides and to degeneration of the nerves. This could be turned to therapeutic advantage. Chronic application of capsaicin to human skin blocks the axon-reflex flare response and the flare response to intradermal allergen and vasoactive inflammatory mediators9. Similarly, application of capsaicin to the nose, under cover of iignocaine to prevent the acute stimulatory effect, produces a long-lasting reduction in the symptoms of rhinitislo. Capsaicin-like drugs, such as olvanil (NE19550), are antinociceptive and anti-inflammatory. They might also be of clinical use in blocking neurogenic inflammation and several such drugs are now under development33. It is possible, however, that depletion and/or degeneration of sensory nerves by capsaicin might have long-term deleterious effects if the tonic release of neuropeptides from these nerves has a trophic or developmental function. Ruthenium red is an inorganic dye that appears to block selectively the Na+-Ca*+ channel opened by capsaicin in sensory nerves. This dye blocks capsaicin-induced activation of sensory nerves and some responses to thermal stimulW35, although it does not block electrically induced release of neuropeptides. This suggests that selective blockade of these nerves is possible, although the effectiveness of such blockers may depend upon the precise mechanism of activation of sensory nerves.

189 Cromoglicate, an anti-asthma drug, may also inhibit activation of sensory nerves, since neurophysiological studies have demonstrated that it reduces the excitation of certain populations of C fibress. A related and more potent drug, nedocromil, is also active in blocking C fibre activation after an initial stimulation37. Another drug that may have an activity on sensory nerves is the loop diuretic furosemide (frusemide), since it blocks bronchoconstriction induced by the irritant metabisulphite aerosoPs and cough induced by inhalation of solutions with low chloride ion concentration39. The precise biochemical mechanism by which these drugs may act on C fibres is not yet understood, however, although they may not act by preventing release of neuropeptides in the same way as opiates. 0

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Neurogenic mechanisms may contribute to several inflammatory diseases; drugs that modulate neurogenic inflammation may therefore have potential clinical value. Recent studies have suggested that several new therapeutic approaches are possible, including blockade of the receptors for the proinflammatory peptides released from sensory nerves, inhibition of release of these peptides from sensory nerves or blockade of nerve activation. Several drugs that act at these different sites of inhibition have now been developed and some of them are suitable for clinical use. It is likely that such therapeutic approaches will prove beneficial in a number of inflammatory diseases, such as asthma, rhinitis, arthritis, gastrointestinal ulceration, cystitis and ocular inflammation.

References 1 Bruce, A. N. (1913) Q. /. Exp. Pkysiol. 6, 339-354 N., Jancs&Gibor, A. and Szolcszinyi, J. (1967) Br. /. Dharmncol. 31, 138-151 SzolcsBnyi, J. (1988) Agents Actions 23, 5-11 Maggi, C. A. and Meli, A. (1988) Gen. Pharmacol. 19, l-43 24, Holtzer, P. (1988) Neuroscience 739-768 Barnes, I’. J. (1986) Lavcef i, 242-245 Stj;ime, P., ,Lundblad, L., Lundberg, J. M. and AnggBrd, A. (1989) Br. 1. Pharmacol. 96, 693-701

2 Jancs6,

3 4 5 6 7

8 Levine, J. D., Dardick, S. J., Roizen, M. F., Helms, C. and Basbaum, A. 1. (1986) /. Newosci. 6, 3423-3429 9 Lundblad. L., Lundberg, L., ,&nggBrd, A. and Zetterstrom. 0. 119851 ENT. I. ‘Pharmacol. 113. 461262 . ~’ IO Wolf, G. (198s) Laryngol. Rhbtol. Ofof. 67.438-445 11 Barth6, L. and SzolcsBnyi. J. (1981) Eur. 1. Pharmacol. 73, 101-104 12 Barth& L., Sebok, B. and Szolcslnyi, J. (1982) Eur. I. Pharmacol. 77.273-279 13 Frossard, N. and Barnes, P. J. (1987) Eur. 1. Phannacol. 141, 519-522 14 Belvisi, M. G., Chung, K. F., Jackson, D. M. and Barnes, P. J. (1988) Br. /. Pharmacof. 95, 41-18 15 Belvisi, M. G., Rogers, D. F. and Barnes, P. J. (1989) /. Appl. Physiol. 66, 268-272 16 Rogers. D. F. and Barnes, P. I. (1989) La%et i, 930-932 17 Jivegard, L. and Svanvik, J. (1988) C!i:;. SC;. 74.219-223 18 Adcock, J. J. and Beesley, J. E. (1989) Am. Rev. Respir. Dis. 139, Al35 19 Grundstrom, N. and Andersson, R. G. G. (1985) Notlnytt-SchmiedeberR’s Arch. Plmnnncol. 328, 23&240 20 Matran, R., Martling, C-R. and Lundberg, J. M. (1989) Eur. /. Pbarmacol.

163, 15-23 21 Stretton, C. D., Belvisi, M. G. and Barnes, P. J. (1989) Br. J. Phnrmacol. 98, 781P 22 Giuliani, S., Maggi, C. A. and Meli, A. (1989) Br. /. Pharmacol. 98, 407-412 23 Belvisi, M. G.. Ichinose. M. and Barnes, P. J. (1989) Br. /. Pharmacol. 97, 1125-1131 24 Giuliani, S., Amann, R., Papini, A. M., Maggi, C. A. and Meli, A. (1989) Ear. J. Phnrmacd. 163, 91-96 25 Gazelius, B., Brodin, C., Olgart. L. and Panopoulos, P. (1981) Acta Vrysiol. Scamf. 113, 155-159 26 Lembeck, F., Donnerer, J. and Barth&L. (1982) Efrr. 1. Pharmacof. 85, 171-176 27 Wei, E. T. and Kiang, J. C. (1989) Ear. J. Phnrmflcol. 168, 81-86 28 Wei, E. T. and Kiang, J. C. (1987) Eur. /. Phnrmacol. 140, 63-67 29 Ichinose, M. and Barnes, P. J. (1989) Ew. J. Pharmncof. 174, 49-55 30 Ichinose, M., Belvisi, M. G. and Barnes, P. J. (1990) /. Appl. Physiol. 68, 21-25 31 Christie, M. J. and North, R. A. (1988) Br. J. Phnrmncol. 95, 896902 32 Ichinose. M. and Barnes, P. J. /. Pharwnco/. Exp. T/w. (in press) 33 Brand, L. et al. (1987) Drrrgs Exp. Ch. Res. 13,259-265 34 Amann, R. and Lembeck. F. (1989) Ew. J. PJ~armncol. 161, 227-279 35 Buckley, T. L., Brain, S. D. and Williams, T. J. (1990) Br. 1. Pkarmocol. 99, 7-8 36 Dixon, M., Jackson, D 3%.and Richards, I. M. (1979) Br. 1. Pharmacol. 67,569-574 37 Jackson. D.. M.,.Norris, A. A. and Eady, R. P. (1989) Pub. Plrnrmacol. 2, 179-184 38 Nichol, G. M. et nl. Am. Rev. Respir. Dis. (in press) 39 Ventresca, C. I’., Nichol. G. M., Barnes. P. J. and Chung, K. F. Am. Rev. Respir. Dis. (in press)

DAMGO: (Tyr-oAla)-Gly-(NMe-Phe)g’yo’ BW443c: HTyr-oArg-Gly-Phe-(NO&-proNH2

Modulation of neurogenic inflammation: novel approaches to inflammatory disease.

Neurogenic inflammation, which involves the release of neuropeptides from capsaicin-sensitive sensory nerves, may contribute to inflammatory diseases ...
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