396 7'horax 1993;48:396-400 Occasional review

A role for capsaicin sensitive, tachykinin Thorax: first published as 10.1136/thx.48.4.396 on 1 April 1993. Downloaded from containing nerves in chronic coughing and sneezing but not in : a hypothesis

J-A Karlsson

Sensory nerves with endings in the airway .'5 These tachykinins, and mucosa mediate respiratory protective reflexes related , are present in a popula- such as coughing, sneezing, mucus secretion, tion of non-myelinated capsaicin sensitive and bronchoconstriction, which are common afferent nerves.5 symptoms of airway disease. Studies in experi- Capsaicin induced release is mental animals suggest that these reflexes preceded by increased cation permeability have unique afferent pathways, though these over the cell membrane. In larger concentra- have been difficult to identify in man. One tions capsaicin is neurotoxic and rapidly caus- pharmacological tool that is increasingly used es death of nerve cells. The tachykinins act on in studies of neural reflexes is capsaicin, the neurokinin 1,2, or 3 receptors (which have pungent agent of hot peppers. Capsaicin highest affinity for , , seems to excite rather selectively a population and , respectively), located on of tachykinin peptide containing, chemosensi- airway and vascular smooth muscle, submu- tive afferent nerves.' 2 cosal glands, parasympathetic nerves, and air- In rodent airways capsaicin produces way epithelium."6 In guinea pigs and rats severe bronchoconstriction and a pro- tachykinin produce bronchoconstric- nounced inflammatory response, which seems tion, vasodilatation, plasma protein leakage to be mediated by substance P, neurokinin A, from the tracheobronchial microcirculation, and possibly other .36 mucus secretion, and facilitation of cholin- Tachykinins contract human bronchi in ergic neurotransmission.'6 These effects are vitro78 and produce bronchoconstriction when mimicked by capsaicin, suggesting an impor- http://thorax.bmj.com/ inhaled by asthmatic subjects.9 The density of tant sensory efferent role for these nerves. substance P immunoreactive nerves'0 and Thus in rodent airways expression of the neurokinin, receptor gene" released from capsaicin sensitive sensory neu- have been reported to be increased in the rones, presumably via an axon reflex,'7 have asthmatic lung. Consequently neuropeptide pronounced bronchoconstrictor and pro- release, via an axon reflex, has been proposed inflammatory actions. to be particularly important in the pathology Interestingly, the most obvious responses of asthma.'2 The proinflammatory effects so to intravascular administration of tachykinins on September 24, 2021 by guest. Protected copyright. apparent in rodents, however, cannot be or capsaicin in the sheep,'8 pig,'9 dog,20 and reproduced even when high doses of capsaicin cat2l are a vasodilator response in the tracheo- are repeatedly inhaled by normal or asthmatic bronchial circulation and mucus secretion.22 subjects6 and capsaicin sensitive nerves seem When present, airway smooth muscle con- unlikely therefore to have a major role in asth- traction in rat, rabbit, ferret, and dog is large- ma. Instead, experimental and clinical data ly mediated through parasympathetic indicate that their most important function in cholinergic pathways.6 In the cat capsaicin the human respiratory tract is to mediate pro- produces a reflex bronchodi2atation. tective reflexes. The hypothesis now is that Furthermore, plasma protein extravasation hyperreactivity in these afferent nerves-that has not been observed in cat or dog airways.24 is, sensory hyperresponsiveness-contributes Hence the characteristic bronchoconstrictor to respiratory symptoms in patients with and proinflammatory effects have not been chronic non-productive cough and non- confirmed in non-rodent animal species. allergic chronic rhinitis.

Discovery Biology, Sensory neuropeptides in human airways Rhone-Poulenc Rorer, Neurokinin containing sensory nerves Human bronchi are contracted by tachykinin Dagenham Research not Centre, Dagenham, and the axon reflex peptides in vitro, neurokinin A-but sub- Essex RMIO 7XS Substance P was first found in guinea pig air- stance P-being more7825potent26 I athanenmrmetha- J-A Karlsson way tissue"3 but we now know that it is also choline and . It has been more Reprint requests to: present in many other species, including difficult to show bronchoconstriction in vivo. Dr J-A Karlsson man.'4 Substance P belongs to a family of Maximum doses of inhaled substance P are Received 22 June 1992 Returned to authors structurally closely related peptides, including without effect on airway tone9 and when 29 July 1992 neurokinin A, neurokinin B, , infused intravenously a predominantly Revised version received 12 October 1992 and neuropeptide gamma, which are derived cardiovascular response was obtained.2' Accepted 5 November 1992 from at least two different preprotachykinin Neurokinin A is 10 times more potent than A rolefor capsaicin sensitive, tachykinin containing nerves in chronic coughing and sneezing but not in asthma: a hypothesis 397

substance P in vitro, which may explain why nounced sneezing, and secretion,"39 patients airways obstruction was induced when a large with vasomotor rhinitis being particularly sen- dose was inhaled by asthmatic subjects.9 The sitive.'9 Secretion induced by capsaicin can be bronchoconstriction was inhibited partly by blocked by a muscarinic antagonist and is nedocromil sodium and partly by an antimus- thus due to a cholinergic parasympathetic Thorax: first published as 10.1136/thx.48.4.396 on 1 April 1993. Downloaded from carinic agent, indicating that neurokinin A reflex.'9 Interestingly, capsaicin induced did not act directly on the smooth muscle.28 29 secretion from the human oral mucosa is also In healthy and asthmatic subjects inhaled mediated through a cholinergic reflex.40 capsaicin caused only transient bronchocon- Despite administration of capsaicin directly striction (for under a minute) which depends on to the nasal mucosa, plasma protein on a parasympathetic cholinergic reflex.'0 extravasation and mediator release could not Endogenous tachykinins, if released, are be detected.4' therefore unlikely to have any noticeable Interestingly, intradermal injection of cap- effects on airway tone in vivo. saicin into human skin produced pain and a It has been speculated that the shedding of local vasodilator response (flare) but not epithelium that occurs in severe asthma and oedema (weal).42 3 The flare is produced by upper respiratory tract viral infections reduces sensory neuropeptides released through an airway neutral endopeptidase activity, which axon reflex and, as in the airways, there is lit- is present in the bronchial mucosa and is the tle evidence of a local inflammatory response major proteolytic enzyme for tachykinins.'6 to capsaicin. Tachykinin mediated changes in Consequently the "braking" mechanism tracheobronchial and nasal blood flow is, would be absent in asthmatic subjects and however, a distinct possibility, which has not endogenous tachykinins would be able to yet been studied in man. exert their proinflammatory effects uninhibit- Thus, whereas studies in rodents strongly ed. Thiorphan, a neutral endopeptidase emphasise the sensory efferent function of inhibitor, would thus be expected to increase capsaicin sensitive sensory nerves, accumulat- basal tone (by potentiating the effect of ing data indicate that at least two major endogenous tachykinins) and augment the effects-that is, bronchoconstriction and effects of inhaled peptides in healthy subjects. extravasation of plasma protein (as measured In asthmatic subjects on the other hand no in the nose)-cannot be reproduced in effect would be expected if neutral endopepti- human subjects. Likewise glandular secretion dase is absent. seems to be mediated via a cholinergic Inhaled thiorphan, however, was found to parasympathetic reflex rather than local have no effect on basal tone but to potentiate release of neuropeptides. inhaled neurokinin A to the same degree in healthy and asthmatic subjects.'132 Nichol http://thorax.bmj.com/ and coworkers33 studied the neutral endo- Sensory afferent role for capsaicin sensi- peptidase inhibitor acetorphan on reflex tive nerves in man bronchoconstriction induced by inhaled Respiratory and cardiovascular reflexes are metabisulphite in asthmatic subjects. triggered by topical application of capsaicin.2 Metabisulphate acts partly via a non-choliner- In guinea pigs, for example, pronounced gic mechanism, but its effect was not altered coughing and sneezing are produced and by acetorphan (though weal and flare induced these reflexes are mediated by afferent path- by substance P were significantly potentiated ways that are separate from those underlying on September 24, 2021 by guest. Protected copyright. in the same subjects).33 These experiments the bronchoconstrictor reflex.244 Coughing were conducted in subjects with mild asthma, cannot be secondary to release of peptides and if shedding of epithelium is proportional because these do not themselves trigger to the severity of the disease, the effect could cough and treatment with the neutral be more pronounced in severe asthma. The endopeptidase inhibitor thiorphan did not present data support the view that endoge- potentiate the cough response, though bron- nous tachykinins are not important for regu- choconstriction was increased.45 Already at lation of bronchial tone in human airways in low (nanomolar) doses aerosolised capsaicin vivo. Clinical studies with the recently devel- causes pronounced coughing, sneezing, and oped potent non-peptide neurokinin receptor secretion in man. Capsaicin induced cough is antagonists,3435 however, will provide further most probably mediated by tachykinins and information on the role of tachykinin peptides C fibre afferents containing calcitonin gene in man. related peptide with endings located in both The effects of local application of central and peripheral airways.46 As in guinea tachykinins and capsaicin on nasal air flow, pigs, in man this response seems not to be leakage of plasma proteins, and secretion due to endogenous tachykinins acting on have been examined in the human nose. The other lung afferents because coughing is not nasal mucosa is readily accessible and, for produced when these peptides are inhaled.9 It example, mediator release and microvascular could be argued that coughing prevented the leakage can be measured non-traumatically. capsaicin aerosol from penetrating deeper A dose of substance P or calcitonin gene into the lung to trigger bronchospasm. related peptide producing systemic vascular Several arguments, however, can be raised effects (vasodilatation) did not induce secre- against this view. Firstly, in guinea pigs tion or nasal blockage36 37 or affect muco- coughing and severe bronchoconstriction ciliary clearance.'8 Capsaicin, on the other occur simultaneously. Secondly, other res- hand, caused a burning sensation, pro- piratory tract irritants, such as , 398 Karlsson

produce both cough and airway obstruction in asthmatic subjects. Finally, even when a Sbcf r .2 7 small particle aerosol is inhaled into peripher- " -- i- ;. al airways no bronchoconstriction is pro- duced.46 Taken together, these findings Thorax: first published as 10.1136/thx.48.4.396 on 1 April 1993. Downloaded from suggest that the afferent function of capsaicin sensitive nerves in the airways is less species specific, and these nerves are likely to sub- serve protective reflexes in the human respira- tory tract.

Sensory hyperresponsiveness Airway or chronic irritation with, for example, cigarette smoke may lead to hyperactivity in capsaicin sensitive afferent nerves, as seen in animal experiments. Prolonged exposure (for 14 days) of guinea pigs to cigarette smoke caused an enhanced sensitivity to the tussive effect of citric acid and thus selectively increased the sensitivity and reactivity of capsaicin sensitive nerves mediating cough.47 The airway content of neuropeptides was increased concomitantly,47 but the bronchoconstrictor response was not altered with this treatment. These data indi- Diagram showing how irritation ofsensory nerves (--- -) cate that chronic airway irritation may lead to with endings in the human respiratory mucosa evokes protective reflexes. Capsaicin sensitive afferent nerves are the development of a sensory hyperrespon- carried mainly in the vagal and laryngeal nervesfrom the siveness that is distinct from bronchial hyper- tracheobronchial tree and in the trigeminal nervefrom the responsiveness. Interestingly, inflammatory nose. Hyperactivity in sensory nerves, as in chronic non- productive cough and non-aUergic chronic rhinitis, may stimuli applied to the skin may increase the lead to sensory hyperresponsiveness. synthesis of tachykinins in sensory nerves and ganglia,48 49 and in experimental chronic arthritis and inflammatory bowel disease the density of substance P immunoreactive nerves has been reported to be increased.5051 http://thorax.bmj.com/ Clinical observations support the existence sensory neurones may have an important role of a sensory hyperresponsiveness: subjects in reflexes protecting the airway and that with cough induced by converting chronic irritation may induce sensory hyper- enzyme inhibitor,52 or with a chronic cough,53 responsiveness has therapeutic implications. as well as subjects with a chronic dry cough,54 At present antimuscarinic drugs, acting post- have an enhanced responsiveness to the tus- junctionally, are used to reduce mucus secre- sive effect of inhaled capsaicin without tion and opiate antitussives to suppress increased bronchoconstrictor responses. activity in a "cough centre" in the central ner- on September 24, 2021 by guest. Protected copyright. Cough is the most common symptom of air- vous system. It would be more attractive to way disease, and in chronic obstructive airway inhibit afferent neural activity directly than to disease and in viral infections of the upper res- inhibit the effects of a range of released piratory tract part of the excessive coughing is neuropeptides. In addition, because different due to a sensory hyperresponsiveness55 (also respiratory reflexes have separate afferent RW Fuller, personal communication). neural pathways an improved efficacy and It was recently shown that obstruction, rhi- selectivity would be anticipated. Studies in norrhoea, and sneezing in patients with non- patients with severe, chronic cough support allergic chronic rhinitis could be significantly this view: despite several treatments, includ- reduced after local treatment with capsaicin ing the use of high dose opiates, only inhaled aerosol that rendered the nerves tachyphylac- local anaesthetics effectively suppressed tic.56 57 These clinical findings suggest an coughing.5859 Similarly, induction of tolerance important role for tachykinin containing sen- with topical capsaicin inhibited symptoms of sory nerves in chronic rhinitis. chronic rhinitis.5657 Capsaicin treatment is Respiratory infections and various forms of painful and a drug inhibiting afferent path- sustained irritation of the respiratory tract ways without having agonist activity obviously may lead to neuropeptide synthesis and would be advantageous. It is tempting to sug- increased afferent activity with sensory hyper- gest that respiratory symptoms during, for responsiveness. Sensory hyperresponsiveness example, upper respiratory tract infections or may explain some of the symptoms in whooping cough would also be reduced by patients with chronic non-productive cough this type of treatment. Afferent neural path- and non-allergic chronic rhinitis (figure). ways in the respiratory tract thus provide new targets for rational drug design and possibly such drugs will become useful in the treat- Therapeutic implications ment of common illnesses of the respiratory The hypothesis that capsaicin sensitive tract. A rolefor capsaicin sensitive, tachykinin containing nerves in chronic coughing and sneezing but not in asthma: a hypothesis 399

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