No abstract

SUMMARY1. With pentobarbitone-anaesthetized cats we have elicited cough reflexes from the tracheobronchial tree and the larynx, and the aspiration and sneeze reflexes from the nasopharynx and the nose respectively. The reflexes were induced by mechanical stimulation of the mucosa, before and during activation of pulmonary C-fibre receptors by intravenous injections of capsaicin or phenylbiguanide.2. During the 20-30 s apnoea due to C-fibre stimulation, the cough reflex from both sites and the sneeze reflex were completely abolished, whereas the aspiration reflex response was approximately halved. Reflex contractions of genioglossus muscle still occurred at this time, but were far weaker than in the control state. 3. During the rapid shallow breathing that immediately followed apnoea due to Cfibre receptor stimulation, the defensive reflexes recovered: the aspiration and sneeze reflexes fully and the cough reflexes to about half of the control response.4. Acute hypotension due to haemorrhage, of a size considerably greater than that due to stimulation of the pulmonary C-fibre receptors, caused no significant inhibition of the cough reflex from the tracheobronchial tree. 5. We conclude that the pulmonary C-fibre reflex powerfully inhibits airway defensive reflexes, and that its activation is unlikely to contribute positively to coughing induced by aerosols of capsaicin and similar agents.

Tussigenic sensitivity of laryngeal and tracheobronchial regions to mechanical and chemical stimuli was compared in 22 urethan-alpha-chloralose-anesthetized dogs. In addition, the contribution of myelinated and unmyelinated vagal fibers in mediating laryngeal and tracheobronchial cough was investigated. The intensity of cough was evaluated from changes in esophageal pressure. Whereas all mechanical stimulations and citric acid inhalations into tracheobronchial region elicited cough, only 56.7% of mechanical stimulation and 33.3% of citric acid challenges to larynx were effective. The intensity of tracheobronchial cough was significantly higher than that of laryngeal cough. When mechanical stimulation was conducted under visual control (bronchofiberscope), cough elicitability was found to be higher from tracheal bifurcation and main stem bronchi (62.5-87.5%) than from any laryngeal structure (0-42.9%). During partial block of vagal conduction (cooling to 6 degrees C), mechanical and citric acid tracheobronchial stimulations failed to elicit cough and mechanical laryngeal stimulation was effective only in 1 of 10 dogs. Intensity of cough was strongly decreased when mechanical stimulation followed capsaicin administration into trachea (0.3 ml; 100 micrograms/ml) or intravenously (10 micrograms/kg). We conclude that, in anesthetized dogs, stimulation of tracheobronchial region is more effective and prompt in eliciting cough than stimulation of larynx, myelinated vagal afferent fibers play an important role in mediating mechanically and citric acid-induced tracheobronchial cough and mechanically induced laryngeal cough, and stimulation of tracheobronchial and pulmonary capsaicin-sensitive receptors strongly inhibits mechanically induced cough.

The cold-sensitive cation channel TRPM8 is a target for menthol, which is used routinely as a cough suppressant and as an additive to tobacco and food products. Given that cold temperatures and menthol activate neurons through gating of TRPM8, it is unclear how menthol actively suppresses cough. In this study we describe the antitussive effects of (-)-menthol in conscious and anesthetized guinea pigs. In anesthetized guinea pigs, cough evoked by citric acid applied topically to the tracheal mucosa was suppressed by menthol only when it was selectively administered as vapors to the upper airways. Menthol applied topically to the tracheal mucosa prior to and during citric acid application or administered continuously as vapors or as an aerosol to the lower airways was without effect on cough. These actions of upper airway menthol treatment were mimicked by cold air delivered to the upper airways but not by (+)-menthol, the inactive isomer of menthol, or by the TRPM8/TRPA1 agonist icilin administered directly to the trachea. Subsequent molecular analyses confirmed the expression of TRPM8 in a subset of nasal trigeminal afferent neurons that do not coincidently express TRPA1 or TRPV1. We conclude that menthol suppresses cough evoked in the lower airways primarily through a reflex initiated from the nose.

Gastro-oesophageal reflux disease (GORD) is one of the most common causes of chronic cough; however, the mechanisms by which GOR initiates coughing are incompletely understood. We address the hypothesis that acidification of oesophagus acutely increases the cough reflex sensitivity in patients with GORD and chronic cough. Nine patients with GORD with chronic cough and 16 patients with GORD without cough were recruited. In a randomized double blind study, saline and acid (HCl, 0.1 mol L(-1)) were separately infused into oesophagus via naso-oesophageal catheter. Cough reflex sensitivity to inhaled capsaicin was determined immediately after completion of each infusion. Infusion of acid into oesophagus increased capsaicin cough reflex sensitivity in patients with GORD and chronic cough. In contrast, acid had no effect on the cough sensitivity in patients with GORD without cough. In a separate study, acid infusion into oesophagus did not affect the cough sensitivity in 18 healthy subjects. We conclude that acid in the oesophagus acutely increases the cough reflex sensitivity to capsaicin in patients with GORD and chronic cough. This phenomenon may contribute to the pathogenesis of cough due to GORD.