Encoding of the cough reflex in anesthetized guinea pigs

Abstract

We have previously described the physiological and morphological properties of the cough receptors and their sites of termination in the airways and centrally in the nucleus tractus solitarius (nTS). In the present study, we have addressed the hypothesis that the primary central synapses of the cough receptors subserve an essential role in the encoding of cough. We found that cough requires sustained, high-frequency (≥8-Hz) afferent nerve activation. We also found evidence for processes that both facilitate (summation, sensitization) and inhibit the initiation of cough. Sensitization of cough occurs with repetitive subthreshold activation of the cough receptors or by coincident activation of C-fibers and/or nTS neurokinin receptor activation. Desensitization of cough evoked by repetitive and/or continuous afferent nerve activation has a rapid onset (<60 s) and does not differentiate between tussive stimuli, suggesting a central nervous system-dependent process. The cough reflex can also be actively inhibited upon activation of other airway afferent nerve subtypes, including slowly adapting receptors and pulmonary C-fibers. The sensitization and desensitization of cough are likely attributable to the prominent, primary, and unique role of N-methyl-d-aspartate receptor-dependent signaling at the central synapses of the cough receptors. These attributes may have direct relevance to the presentation of cough in disease and for the effectiveness of antitussive therapies.

Selective inhibition of vagal afferent nerve pathways regulating cough using Nav 1.7 shRNA silencing in guinea pig nodose ganglia

“…This is not a surprising result, inasmuch as our previous work indicates that cough in anesthetized guinea pigs is very sensitive to the number of units activated in response to a stimulus and the peak action potential frequency in these active units (8). Functionally reducing the number of vagal afferents activated by ϳ50% (through unilateral vagotomy) or reducing the peak action potential frequencies (evoked electrically) to Ͻ10 Hz markedly inhibited or abolished coughing in most animals.…”

Brainstem mechanisms underlying the cough reflex and its regulation

“…Blockade of NMDA receptors by 10 mM D-AP5 strongly reduced, but did not completely suppress cough responses. An essential contribution of EAA receptors in the mediation of cough afferent inputs within the NTS has been observed in guinea pigs, but in regions more rostral and lateral to the commissural subnucleus and with a predominant role of NMDA receptors (Canning and Mori 2011). Recently, Poliacek et al (2017) found in the cat that bilateral microinjections of kynurenic acid into the cNTS were without effects, whilst similar microinjections into the rostral NTS caused marked alterations in both baseline respiratory activity and cough motor pattern.…”

Tachykinin: recent developments and novel roles in health and disease

“…Various endogenous and exogenous factors are involved in the cough reflex, with afferent C-fiber activation in the airways being insufficient itself to induce the cough reflex. However, the micro injection of SP in the commissural subnucleus of the nucleus of the solitary tract (NST) enhances cough reflex sensitivity to topical citric acid exposure in the guinea pig trachea (149), indicating that signals inducing the cough reflex through C-fibers coming from the airways converge in the NST, and NKR is involved in the regulation of the reflex threshold.…”