Lidocaine, a non–selective inhibitor of voltage-gated sodium channels, blocks chemically-induced cough in awake naïve Guinea pigs

Abstract

Pathological cough is an unwanted and debilitating symptom of a range of chronic respiratory diseases. Currently used antitussive therapies are ineffective and act largely through the central nervous system, having a number of dangerous adverse effects. There is an urgent need for new, better peripherally acting antitussive drugs with minimal adverse effects. Significant progress has recently been achieved in the understanding of voltage-gated sodium channels (NaVs), which points to the biological plausibility that blocking specific NaV sybtypes (NaV1.1 – NaV1.9) in the airway sensory nerves may lead to the inhibition of pathological coughing. In this study we investigated the effect of lidocaine, a non–selective NaVs blocker, on citric acid– and capsaicin–induced cough in the awake naïve guinea pig experimental model. We found that pre–inhalation followed by continuous inhalation of nebulized lidocaine (10 mM) during citric acid (0.8 M) cough challenge was effective in suppressing the cough response (number of coughs, median [IQR]) – (5 [3.8–6.3] pre–lidocaine vs. 1 [0.3–3.8] post–lidocaine; p = 0.002, n = 11). Likewise, lidocaine during capsaicin (50 μM) cough challenge reduced the number of coughs (6 [4.1–7.9] pre–lidocaine vs. 1 [0.5–1.5] post–lidocaine; p = 0.0005, n = 12). We conclude that nebulized lidocaine effectively blocks chemically induced cough. These findings lend support to the notion that NaVs may become a novel neural target in antitussive treatment.