Encoding of the cough reflex

Abstract

Coughing can be both voluntarily induced and involuntarily initiated by activation of vagal afferent nerves innervating the airways and lungs. Centrally, cough is regulated at the level of the brainstem through integration of vagal afferent nerve input by relay neurones in the nucleus tractus solitarius (nTS). Projections to and from the nTS add further complexity to cough regulation, as do the profound influences of psychological and social factors known to regulate cough. Peripherally, both neuronal and non-neuronal elements in the airways regulate the excitability of the vagal afferent nerve terminals regulating cough. These multiple levels of integration and encoding of the cough reflex may render this defensive respiratory response highly susceptible to modulation both by disease processes and through therapeutic intervention.

Fig. 1

Coughing and increased respiratory rate evoked by electrically stimulating the tracheal mucosa of anaesthetized guinea pigs. A custom-built electrode was positioned onto the tracheal mucosa as previously described [40]. Following an equilibration period, four consecutive stimulations consisting of 200 square pulses delivered at 2, 5, 10 and 20 Hz (over consecutive and contiguous time periods of 100, 40, 20 and 10 s, respectively) were delivered while recording A) respiratory rate and B) the cumulative number of coughs evoked. Only when the stimulation frequency reached 20 Hz did all five animals cough (0, 2 and 4 of five animals coughed during stimulation at 2, 5 and 10 Hz, respectively). Respiratory rate increased in all guinea pigs stimulated at 5 Hz Panel C shows the stimulation frequencies and stimulation durations.

Fig. 2

Potentiation of bradykinin evoked coughing in conscious guinea pigs following pretreatment with the peptidase inhibitors captopril and thiorphan. Both compounds (0.1 mM) were delivered via aerosol to guinea pigs for 5 min prior to bradykinin challenge. Control animals were similarly pretreated with the vehicle for captopril and thiorphan (saline). Bradykinin challenges were given over 10 min and the total number of coughs evoked was recorded. In the absence of the peptidase inhibitors, the concentration of bradykinin required to evoke coughing was =5 mg/ml. Each bar represents the mean±sem of five experiments.

Fig. 3

Trypsin potentiates TRPV1-dependent A) inward currents in isolated rat bronchopulmonary C-fibres studied using patch clamp techniques and B) coughing in awake guinea pigs. A PAR2 receptor selective agonist mimicked the effects of trypsin. Each bar represents the mean ± sem of at least eight experiments. Data modified from [13,14].

Fig. 4

Inhibition of airway afferent nerve activation studied in vitro (panels A and C) and coughing evoked in vivo (panels B and D) in guinea pigs. A) Mexiletine reduces the number of action potentials and the peak frequency of activation evoked by citric acid in vitro in studies of nodose ganglia neurones projecting to the guinea pig trachea (n=4). Mexiletine was without effect on threshold sensitivities of these afferents to acid or to mechanical stimulation or their responsiveness to electrical stimulation (data not shown; Figure modified from Carr, 2006). B) Mexiletine markedly inhibits coughing evoked by citric acid, applied topically to the tracheal mucosa of anaesthetized guinea pigs. C) The peptide neurotransmitter nociceptin inhibits the TRPV1-dependent inward currents evoked by acid in isolated airway afferent neurones studied in vitro using patch clamp techniques. Nociceptin was without effect on the TRPV1-independent (amiloride-sensitive) inward currents evoked by acid (data not shown). D) In vivo, nociceptin inhibited citric acid evoked coughing in awake guinea pigs. Data in panels C and D are modified from [26] and are the mean±sem of 5–10 experiments.

Fig. 5

General anaesthesia (urethane, 1.5 g/ kg) completely abolishes bradykinin-evoked coughing in guinea pigs (n=5–12). Anaesthetized guinea pigs cough readily in response to electrical or mechanical stimulation of the laryngeal, tracheal or bronchial mucosa or to acid applied topically to the tracheal mucosa (see Figs. 1 and 4; also see [40]). The effects of anesthesia on cough seem to be selective for coughing dependent upon C-fibre activation. Representative traces of the response to bradykinin in awake and anaesthetized guinea pigs are shown in panels A and B respectively. The mean data from these experiments are presented in panel C. Figure reproduced with permission from [40].