Peripheral neural circuitry in cough

Abstract

Cough is a reflex that serves to protect the airways. Excessive or chronic coughing is a major health issue that is poorly controlled by current therapeutics. Significant effort has been made to understand the mechanisms underlying the cough reflex. The focus of this review is the evidence supporting the role of specific airway sensory nerve (afferent) populations in the initiation and modulation of the cough reflex in health and disease.

Figure 1

The distribution and responsiveness of airway afferent subtypes in the guinea pig. RARs, rapidly adapting receptors; SARs, slowly adapting receptors. Taken from [5].

Figure 2

Airway afferent subtypes have distinct sensitivities to various stimuli. A, representative recordings from tracheal afferents originating in the nodose ganglia (Aδ fiber) and jugular ganglia (C fiber) of guinea pigs. Responses to capsaicin (1µM), 0.1M citric acid and von Frey fiber punctate mechanical force are shown. Adapted from [1]. B, representative recordings from afferents originating in the nodose ganglia (C fiber) and jugular ganglia (C fiber) innervating the guinea pig lung. Responses to ATP (30µM), α,β-methylene ATP (30µM) and capsaicin (0.3µM) are shown. Adapted from [18].

Figure 3

Distinct afferent subtypes mediate cough. A and B, the effect of in vivo knockdown of NaV1.7 in nodose neurons on (A) the cough evoked by punctate mechanical stimulation of the trachea in anesthetized guinea pigs, and (B) the cough evoked by inhalation of nebulized capsaicin (10µM) in conscious animals. The number of animals in each group is denoted in parentheses. C, Coughs evoked by various C fiber stimuli in conscious guinea pigs: saline (n=8), adenosine (10mM, n=6), 2-methyl-5HT (5mM, n=5), ATP (10mM, n=5), capsaicin (3µM, n=8) and AITC (10mM, n=5). Adapted from [30].

Figure 4

Capsaicin-induced calcium responses in tracheal-specific nodose neurons in control and BDNF-treated guinea pigs. A: representative example of the Ca2+ responses, as measured by fura-2, in a tracheal-specific nodose neuron isolated from guinea pigs 2 wk following treatment with Matrigel alone (control, gray line) or treated with Matrigel containing 200 ng/ml BDNF (black line). Capsaicin (1µM) was applied for 60 s (black arrow). B: percentage of tracheal-specific nodose neurons from control animals (n = 4 ganglia) and BDNF-treated animals (n = 4 ganglia) that responded to capsaicin. Taken from [28].