Abstract
The α3β4 nicotinic acetylcholine receptor (nAChR) subtype is widely expressed in the peripheral and central nervous systems, including in airway sensory nerves, which transduce the irritant effects of nicotine in tobacco smoke, and in certain brain areas that may be involved in nicotine addiction and/or withdrawal. Menthol, a widely used additive in cigarettes, is a potential analgesic and/or counterirritant at sensory nerves and may also influence nicotine's actions in the brain. We examined menthol's effects on recombinant human α3β4 nAChRs and native nAChRs in mouse sensory neurons. Menthol markedly decreased nAChR activity as assessed by Ca2+ imaging, 86Rb+ efflux and voltage-clamp measurements. Co-application of menthol with acetylcholine or nicotine increased desensitization, demonstrated by an increase in the rate and magnitude of the current decay and a reduction of the current integral. Pretreatment with menthol followed by its washout did not affect agonist-induced desensitization, suggesting that menthol must be present during the application of agonist to augment desensitization. Importantly, the effects of menthol increased with agonist concentration but exhibited neither voltage-sensitivity nor use-dependence characteristic of open-channel blockade. Interestingly, menthol slowed or prevented the recovery of nAChRs from desensitization indicating that it does not act as a typical competitive antagonist or channel blocker but instead probably stabilizes a desensitized state. Moreover, menthol at concentrations up to 1 mM did not compete for the orthosteric nAChR binding site labeled by [3H]-epibatidine. Taken together, these data indicate that menthol promotes desensitization of α3β4 nAChRs by an allosteric action.
- The American Society for Pharmacology and Experimental Therapeutics