Activation of the cold-receptor TRPM8 by low levels of menthol in tobacco products

Activation of the cold-receptor TRPM8 by menthol or other tobacco additives can suppress natural defense reactions such as coughing that usually would become effective as involuntary resistance against the inhalation of fumes. In Europe menthol is only regulated as flavor, but can be used as additive as long as no characteristic mint-like aroma will become noticeable in the end-product tobacco. The question needs to be addressed of whether such comparatively minor contents would be sufficient to trigger a measurable activation of TRPM8. In this study, we have analyzed both the contents of menthol and other natural TRPM8 agonists in tobacco products and developed a bioassay to determine the minimum concentrations of selected agonists to activate the TRPM8 receptor in cultured cells. The data confirm menthol as strongest natural agonist investigated. Based on these experiments and previously published data, we have estimated both the minimum menthol concentrations in cigarette smoke and in tobacco that are expected to trigger measurable physiological effects. According to our assessments, TRPM8 activation is likely to occur when cigarettes contain more than 50 micrograms of menthol. Importantly, menthol contents in cigarettes far below the typical levels that require declaration as "mentholated" would be sufficient to activate sensory receptors.