Identification of the tracheal and laryngeal afferent neurones mediating cough in anaesthetized guinea‐pigs

Abstract

We have identified the tracheal and laryngeal afferent nerves regulating cough in anaesthetized guinea-pigs. Cough was evoked by electrical or mechanical stimulation of the tracheal or laryngeal mucosa, or by citric acid applied topically to the trachea or larynx. By contrast, neither capsaicin nor bradykinin challenges to the trachea or larynx evoked cough. Bradykinin and histamine administered intravenously also failed to evoke cough. Electrophysiological studies revealed that the majority of capsaicin-sensitive afferent neurones (both Aδ-and C-fibres) innervating the rostral trachea and larynx have their cell bodies in the jugular ganglia and project to the airways via the superior laryngeal nerves. Capsaicin-insensitive afferent neurones with cell bodies in the nodose ganglia projected to the rostral trachea and larynx via the recurrent laryngeal nerves. Severing the recurrent nerves abolished coughing evoked from the trachea and larynx whereas severing the superior laryngeal nerves was without effect on coughing. The data indicate that the tracheal and laryngeal afferent neurones regulating cough are polymodal Aδ-fibres that arise from the nodose ganglia. These afferent neurones are activated by punctate mechanical stimulation and acid but are unresponsive to capsaicin, bradykinin, smooth muscle contraction, longitudinal or transverse stretching of the airways, or distension. Comparing these physiological properties with those of intrapulmonary mechanoreceptors indicates that the afferent neurones mediating cough are quite distinct from the well-defined rapidly and slowly adapting stretch receptors innervating the airways and lungs. We propose that these airway afferent neurones represent a distinct subtype and that their primary function is regulation of the cough reflex.

Cough and ventilatory adjustments evoked by aerosolised capsaicin and distilled water (fog) in man

“…On the other hand, the ventilatory effects produced by RARs stimulation mainly consist of hyperpnoea (Coleridge and Coleridge, 1986). The putative specific cough receptors described recently in the guinea pig, if present in humans, could be excited by fog and, indirectly, by capsaicin (Canning et al, 2004;Mazzone, 2004Mazzone, , 2005Mazzone et al, 2005). Unfortunately, no information is available on the reflex ventilatory effects provoked by its activation.…”

“…The C-fibre receptors have also been implicated (Lee and Pisarri, 2001;Widdicombe, 2001). Recently, a peculiar type of low-threshold mechanoreceptors has been described in the guinea pig extrapulmonary airways and has been suggested to be the actual cough receptor (Canning et al, 2004;Mazzone, 2005;Mazzone et al, 2005). Although several in vivo experiments (Pisarri et al, 1991(Pisarri et al, , 1992Mohammed et al, 1993) indicate that in many animal species both the airway RARs and C-fibre receptors are activated by non-isosmolar solutions and capsaicin, a direct involvement of the latter sensor type in cough mediation is controversial (e.g., Widdicombe, 2001;Lee and Pisarri, 2001).…”

“…Indeed, recent lines of evidence suggest a modifying and amplifying role for capsaicin-sensitive nerves in cough and other defensive reflexes in awake animals (Canning et al, 2006). Interestingly, it has been proposed that sensory nerve activation by inhaled irritants could also result in 'sensitisation' of central excitatory pathways regulating the cough reflex (Canning et al, 2004;Mazzone et al, 2005). Admittedly, present knowledge on the role played by the various types of airway sensors in the mediation of the observed respiratory responses is scanty, and it can only be speculated in our experimental conditions.…”

“…Animal experiments performed in vivo have revealed that RARs and C-fibre sensory receptors may be activated by both non-isotonic water solutions and capsaicin, albeit to different extents (Pisarri et al, 1991(Pisarri et al, , 1992Mohammed et al, 1993;Morikawa et al, 1997), and many inhalation studies have confirmed the powerful tussigenic action of these agents in normal subjects and in patients with respiratory and nonrespiratory disorders (Higenbottam et al, 1989;Fontana et al, 1997Fontana et al, , 1998Fontana et al, , 1999aDavenport et al, 2002;Kastelik et al, 2002;Dicpinigaitis, 2004). A peculiar type of low-threshold mechanoreceptors innervated by myelinated vagal fibres has been described recently in the guinea pig extrapulmonary airways (Canning et al, 2004;Mazzone, 2005;Mazzone et al, 2005). This sensor type has been suggested to represent the actual 'cough receptor' (Mazzone, 2005).…”

Experimental models and mechanisms of enhanced coughing

“…Model of the peripheral and central elements of the neurogenic mechanism for cough, highlighting the proposed effects of inflammation. The model is modified from Bolser and Davenport [29] and depicts: (a) augmented tracheal cough receptor [30] activity, (b) laryngeal cough receptors, (c) tracheal and laryngeal relay neurones (interneurones), (d) convergent relay neurones in the NTS and medial reticular formation that receive synaptic input from both tracheal and laryngeal interneurons, (e) a tracheobronchial gating mechanism, (f) a laryngeal gating mechanism that is functionally subdivided into elements controlling excitability of the cough/respiratory pattern generator [31] and the magnitude of expiratory motor drive, and (g) inspiratory and expiratory premotor neurons. Pulmonary slowly adapting stretch receptors facilitate laryngeal cough and have a permissive effect on tracheobronchial cough [32,33].…”