Neurophysiology of the cough reflex.

We read with much interest the recent review "Neurophysiology of the cough reflex" by WIDDICOMBE [1], which appeared in the July issue of the Journal. The review gave a detailed account of afferent nerves in the airways, with particular reference to those that may directly or indirectly be involved in the cough reflex. Based primarily on data with select irritants which trigger electrical activity in sensory nerves and cough in cats and dogs, the author concludes that thin, myelinated, rapidly adapting stretch receptors (RARs), "irritant receptors", uniquely mediate the cough reflex and that lung C-fibres suppress coughing. In our opinion, published experimental data in guineapig and man indicate instead that both RARs and bronchial C-fibres are important in mediating the cough reflex. The following observations support a direct role for bronchial C-fibres in cough. Firstly, capsaicin is a relatively selective stimulus of C-fibres compared with RARs and slowly adapting stretch receptors (SARs). Low doses of capsaicin trigger cough when inhaled by conscious guinea-pigs and human subjects. Electrophysiological recordings of afferent neural activity from a guinea-pig tracheobronchial preparation demonstrate that capsaicin stimulates C-fibres but not A-δ fibres (RARs) [2]. Capsaicin is also a more potent stimulant of C-fibres than RARs in the cat [3] and dog [4]. Importantly, capsaicin causes a burst of activity in Cfibres, which are normally silent, whereas it merely potentiates a pre-existing spontaneous discharge in myelinated fibres [3, 4]. Secondly, capsaicin-pretreatment of guinea-pigs (causing degeneration of a population of chemosensitive Cfibre afferents) inhibits coughing due to capsaicin and citric acid, but not that due to cigarette smoke, histamine and mechanical stimulation, indicating that different types of afferent nerves can directly mediate this reflex [5]. Interestingly, nicotine and histamine have been shown to stimulate RARs in guinea-pigs [6]. Thirdly, chronic exposure of guinea-pigs to cigarette smoke selectively enhances the sensitivity of capsaicin-sensitive C-fibres mediating cough, and increases the neuropeptide content of airway nerves, whilst leaving the bronchoconstrictor response unaffected [7]. At the same time, the cough response to cigarette smoke is unchanged, suggesting a selective upregulation of capsaicin-sensitive Cfibres. Fourthly, although capsaicin releases tachykinins and calcitonin gene-related peptide (CGRP) from C-fibres via an axon-reflex, it is unlikely that they activate airway RARs and, thereby, indirectly trigger the cough reflex. Inhaled tachykinin peptides do not cause cough in healthy subjects [8], and when thiorphan (an inhibitor of neutralendopeptidase metabolism of tachykinins) is inhaled by human subjects, reportedly only the bronchoconstrictor response to neurokinin A is enhanced [9]. Similarly, in guinea-pigs, we found that, thiorphan enhanced the citric acid-induced bronchospasm but not the cough response [10]. One study has reported that thiorphan potentiates the cough response to substance P (SP) but the significance of this finding is difficult to assess since very low concentrations of SP (10-19 to 10-16 M) were studied, coughing was measured up to 13 min after a 2 min aerosol exposure, and the ethanol vehicle also produced coughing [11]. It was recently shown that a neurokinin-1 (NK1)-receptor antagonist does not inhibit hypertonic saline-induced cough in asthmatic subjects [12]. Finally, guinea-pig and human [13] bronchi are more sensitive to the tussive effect of inhaled C-fibre stimulants than the larynx and central airways, which is consistent with the distribution of unmyelinated bronchial C-fibres predominantly to intrapulmonary airways. The pulmonary chemoreflex, characterized by apnoea, bradycardia and hypotension, is mediated via pulmonary Cfibres. As described in the review, stimulation of these fibres inhibits cough, which is only to be expected when the respiratory rhythm generator in the central nervous system (CNS) is suppressed during the apnoea. Furthermore, the cough reflex would of course not be effective as a defense mechanism if evoked from the respiratory bronchioles and alveoli, which seems to be the site of these particular sensory nerve endings. Cough is an important clinical problem, not only in subjects with chronic cough but also in asthma, since it can be an early, and sometimes the only, sign of disease. We agree with WIDDICOMBE [1] that RARs mediate the cough reflex and that pulmonary C-fibres may be inhibitory, but in our opinion a wealth of experimental data support a direct role for bronchial C-fibres in cough. Sensory hyperresponsiveness in capsaicin-sensitive bronchial C-fibre afferents is a characteristic feature of chronic cough (see [14]) and, inferentially, identification of neural pathways in airway reflexes may lead to a better understanding of the pathophysiology of airway diseases, including asthma, as well as to the development of more efficacious therapeutic agents.