Influence of combined voltage-gated sodium channel NaV1.7 and NaV1.8 inhibitors on cough in a guinea pig model

Pathological excessive cough is a serious clinical problem in many patients. It is no doubt that an increased activation and sensitization of airway vagal C-fibres in disease stems from dysregulation of the neural pathways that control cough. Due to the limited efficacy and unwanted side effects of current antitussives, there is a continual demand for the development of a novel more effective antitussive. Since voltage-gated sodium channels (Na(V)s) are absolutely required for action potentials initiation and conduction irrespective of the stimulus, Na(V)s became a promising and attractive neural target. Current studies establish that Na(V)1.7 and Na(V)1.8 inhibitors have the potential to suppress cough. In this study, we demonstrated that inhaled aerosol of Na(V)1.7 inhibitor PF-05089771 (10 mu M) and Na(V)1.8 inhibitor A-803467 (1 mM) mixture inhibited the capsaicin-induced cough by approximate to 60 % and citric acid-induced cough by approximate to 65 % at doses that did not modify respiratory rate. Our previous and present studies indicate that Na(V)1.7 and Na(V)1.8 may present promising therapeutic targets for antitussive therapy.