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Received June 21, 2005
Revised July 12, 2005
Accepted after revision July 26, 2005
1 Johns Hopkins Asthma and Allergy Center, Baltimore, MD.
* To whom correspondence should be addressed. E-mail: bjc{at}jhmi.edu.
Cough initiated from the trachea and larynx in anaesthetized guinea-pigs is mediated by capsaicin- insensitive, mechanically-sensitive vagal afferent neurones. Tachykinin-containing, capsaicin-sensitive C- fibres also innervate the airways and have been implicated in the cough reflex. Capsaicin-sensitive nerves act centrally and synergistically to modify reflex bronchospasm initiated by airway mechanoreceptor stimulation. The hypothesis that polymodal mechanoreceptors and capsaicin-sensitive afferent nerves similarly interact centrally to regulate coughing was addressed in this study. Cough was evoked from the tracheal mucosa either electrically (16Hz, 10 sec trains, 1-10V) or by citric acid (0.001-2M). Neither capsaicin nor bradykinin evoked cough when applied to the trachea of anaesthetized guinea-pigs, but substantially reduced the electrical threshold for initiating the cough reflex. The TRPV1 receptor antagonist capsazepine prevented the increased cough sensitivity induced by capsaicin. These effects of topically applied capsaicin and bradykinin were not due to interactions between afferent nerve subtypes within the tracheal wall or a direct effect on the cough receptors, as they were mimicked by nebulizing 1mg/mL bradykinin into the lower airways or by microinjecting 0.5nmol capsaicin into the commissural nucleus of the solitary tract (nTS). Citric acid induced coughing was also potentiated by inhalation of bradykinin. The effects of tracheal capsaicin challenge on cough were mimicked by microinjecting substance P (0.5-5nmol) into the nTS and prevented by intracerebroventricular administration (20nmol/ hr) of the neurokinin receptor antagonists CP99994 or SB223412. Tracheal application of these antagonists was without effect. C-fibre activation may thus sensitize the cough reflex via central mechanisms.
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