Beneficial effects of menthol are mediated via a TRPM8-independent mechanism

Abstract

Asthma is a debilitating disease of the airways characterised by symptoms such as bronchoconstriction, hyperresponsiveness and cough. Current therapies are ineffective in severe disease highlighting the need for novel treatments. Menthol, a cooling compound found in medicinal products and several OTC medications, is commonly thought to activate the Transient Receptor Potential Melastatin 8 (TRPM8) channel and has been reported to possess beneficial effects such as bronchodilation and suppression of cough, however the mechanism of action is unknown. The aim was to study the beneficial properties of menthol in the airways and investigate the role of TRPM8. TRPM8 was expressed in mouse and guinea pig (GP) vagal ganglia. Using a TRPM8 antagonist (JNJ41876666) and Trpm8 -/- mice in an isolated vagal nerve preparation we showed that both WS3 (TRPM8 agonist) and (-)-menthol caused a small activation of human, GP and mouse vagal nerves which was TRPM8 dependent. Interestingly, pre-incubation of (-)-menthol inhibited vagal nerve activation induced by the tussive stimulus, capsaicin, an effect that was not inhibited by JNJ41876666. WS3 and (-)-menthol caused relaxation of human, mouse and GP trachea, which was not abolished by JNJ41876666 nor in the Trpm8 -/- mouse airway. No expression of TRPM8 was detected in human, GP or mouse airway smooth muscle. (-)-menthol caused a small TRPM8-dependent activation but a robust TRPM8-independent inhibition of vagal sensory nerve activity and relaxation of airway smooth muscle. Elucidating the mechanism behind the beneficial effects of (-)-menthol could lead to the development of promising new therapeutic targets for airway diseases such as asthma.