Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism

Abstract

Background Nicotine is a major oral irritant in smokeless tobacco products and has an aversive taste. Mentholated smokeless tobacco products are highly popular, suggesting that menthol increases their palatability and may facilitate initiation of product use. While menthol is known to reduce respiratory irritation by tobacco smoke irritants it is not known whether this activity extends to oral nicotine and its aversive effects. Study design The two-bottle choice drinking assay was used to characterize aversion and preference in C57BL/6 mice to a range of menthol concentrations (10–200 μg/ml). Then, effects of menthol on oral nicotine aversion were determined. Responses were compared with those in mice deficient in the cold/menthol receptor, TRPM8, expressed in trigeminal sensory neurons innervating the oral cavity. Results Mice showed aversion to menthol concentrations of 100 μg/ml and above. When presented with a highly aversive concentration of nicotine (200 μg/ml), mice preferred solutions with 50% or 100 μg/ml menthol added over nicotine alone. In contrast to wild-type mice, Trpm8−/− showed a strong aversion to mentholated (100 μg/ml) nicotine (200 μg/ml) and preferred nicotine alone. Trpm8−/− mice show aversion to lower concentrations of menthol than wild-type mice. Conclusions Oral menthol can reduce the aversive effects of oral nicotine and, at higher concentrations, acts as an irritant by itself. Menthol’s effects in relation to nicotine require TRPM8, the cool temperature sensing ion channel that activates analgesic and counterirritant mechanisms. These mechanisms may underlie preference for menthol-containing smokeless tobacco products and may facilitate initiation of product use.

Menthol disrupts nicotine’s psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice

“…This increase was unexpected since 10 μg/ml menthol had no effect on water intake in acute studies, and became aversive at higher concentrations [27]. Although menthol does not affect water intake following acute administration, it is possible that tolerance to some aspects of menthol response over time could lead to a preference for menthol following chronic administration.…”

“…The pH of all solutions was adjusted to 7. The concentration of nicotine was based on previous studies [21, 25, 26] and menthol concentration was based on pilot studies showing no baseline preference for this concentration in acute administration, with higher menthol concentrations becoming aversive [27]. This concentration corresponds to a menthol to nicotine ratio similar to what is found in un-mentholated cigarettes [28].…”

Oral thermosensing by murine trigeminal neurons: modulation by capsaicin, menthol, and mustard oil

“…Mice avoid drinking aqueous solutions of capsaicin above 1.65 μM but do not completely reject even 330 μM capsaicin solutions (Simons et al 2001). Mice reduce drinking of menthol solutions above 640 μM but still consume menthol at twice that concentration (Fan et al 2016). We are unaware of data on mice consuming AITC solutions.…”

Studying the interactive effects of menthol and nicotine among youth: An examination using e-cigarettes

“…For example, menthol produces analgesic and cooling sensations via activation of the TRPM8 receptors (Hatem et al, 2006; Wasner et al, 2004), and alters irritant responses via the TRPA1 receptor, which also mediates irritant responses to nicotine (Fan et al, 2016; Karashima et al, 2007; Xiao et al, 2008). Menthol also modulates nicotinic receptor (nAChR) function (Hans et al, 2012; Ton et al, 2015).…”