Regulation of Cough by Voltage-Gated Sodium Channels in Airway Sensory Nerves

Chronic cough is a significant clinical problem in many patients. Current cough suppressant therapies are largely ineffective and have many dangerous adverse effects. Therefore, the identification of novel therapeutic targets and strategies for chronic cough treatment may lead to development of novel effective antitussive therapies with fewer adverse effects. The experimental research in the area of airway sensory nerves suggests that there are two main vagal afferent nerve subtypes that can directly activate cough – extrapulmonary airway C-fibres and Aδ-fibres (described as cough receptors) innervating the trachea. There are different receptors on the vagal nerve terminals that can trigger coughing, such as TRP channels and P2X2/3 receptors. However, in many patients with chronic respiratory diseases multiple activation of these receptors could be involved and it is also difficult to target these receptors. For that reason, a strategy that would inhibit cough-triggering nerve afferents regardless of activated receptors would be of great benefit. In recent years huge progress in understanding of voltage-gated sodium channels (NaVs) leads to a hypothesis that selective targeting of NaVs in airways may represent an effective treatment of pathological cough. The NaVs (NaV1.1 – NaV1.9) are essential for initiation and conduction of action potentials in these nerve fibres. Effective blocking of NaVs will prevent communication between airways and central nervous system and that would inhibit provoked cough irrespective to stimuli. This review provides an overview of airway afferent nerve subtypes that have been described in respiratory tract of human and in animal models. Moreover, the review highlights the current knowledge about cough, the sensory nerves involved in cough, and the voltage-gated sodium channels as a novel neural target in regulation of cough.