Multiple pharmacological actions of centrally acting antitussives--Do they target G protein-coupled inwardly rectifying K⁺ (GIRK) channels?

Antitussive drugs have been used for decades and their modes of action are well elucidated. However, recent studies on the mechanism of their antitussive action seem to be opening a new way for discovery or development of novel drugs for intractable brain diseases including psychiatric disorders. Antitussives inhibit the currents caused by activation of G protein-coupled inwardly rectifying K⁺ (GIRK) channels in neurons. In our own studies carried out so far, we found that antitussives possessing an inhibitory action on GIRK channels, similar to the effects of an enriched environment, ameliorate symptoms of intractable brain diseases in various animal models. In this review, the multiple pharmacological actions of the antitussives are described, and their mechanisms are discussed addressing GIRK channels as a possible molecular target.