Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants

Abstract

Menthol, the cooling agent in peppermint, is added to almost all commercially available cigarettes. Menthol stimulates olfactory sensations, and interacts with transient receptor potential melastatin 8 (TRPM8) ion channels in cold-sensitive sensory neurons, and transient receptor potential ankyrin 1 (TRPA1), an irritant-sensing channel. It is highly controversial whether menthol in cigarette smoke exerts pharmacological actions affecting smoking behavior. Using plethysmography, we investigated the effects of menthol on the respiratory sensory irritation response in mice elicited by smoke irritants (acrolein, acetic acid, and cyclohexanone). Menthol, at a concentration (16 ppm) lower than in smoke of mentholated cigarettes, immediately abolished the irritation response to acrolein, an agonist of TRPA1, as did eucalyptol (460 ppm), another TRPM8 agonist. Menthol's effects were reversed by a TRPM8 antagonist, AMTB. Menthol's effects were not specific to acrolein, as menthol also attenuated irritation responses to acetic acid, and cyclohexanone, an agonist of the capsaicin receptor, TRPV1. Menthol was efficiently absorbed in the respiratory tract, reaching local concentrations sufficient for activation of sensory TRP channels. These experiments demonstrate that menthol and eucalyptol, through activation of TRPM8, act as potent counterirritants against a broad spectrum of smoke constituents. Through suppression of respiratory irritation, menthol may facilitate smoke inhalation and promote nicotine addiction and smoking-related morbidities.

Sensory Effects of Menthol and Nicotine in an E-Cigarette

“…21,22 Evidence from the studies in mice also indicate that menthol's inhibitory effects depend upon TRPM8, which has been shown to underlie the analgesic effects of cold on acute and inflammatory pain via an opioid-dependent central neural pathway. 49 An analgesic action of menthol via a central neural mechanism raises the possibility that menthol stimulation in both the upper and lower airways may contribute to reducing the sensory irritation of nicotine that is sensed most acutely in the throat and lungs.…”

“…The authors of a recent study of menthol cigarettes concluded there was no consistent effect of menthol on perceived harshness and overall impact, 20 whereas a previous study indicated that menthol could either increase or decrease the perceived harshness of a cigarette depending on nicotine concentration. 8 Studies in mice 21,22 indicate that menthol can reduce the sensory irritation from constituents of cigarette smoke, including nicotine, that stimulate the pain receptor TRPA1, 23,24 which has been shown to play a role in cough. 25 However, the numerous other chemical and particulate irritants in tobacco smoke 5,26 have precluded direct measurement of the effect of menthol on the perception of nicotine irritation alone.…”

Menthol Enhances the Desensitization of Human α3β4 Nicotinic Acetylcholine Receptors

“…The consequences of this effect are not known with certainty, but one possibility is that it could offset the irritant effects of nicotine in the airways, allowing cigarette smoke to be inhaled deeper into the lungs and held there for a longer time. Thus, the known analgesic effects of menthol, acting via sensory nerve TRPM8 (Willis et al, 2011) and TRPA1 channels, may be augmented by enhanced desensitization of sensory nerve nAChRs.…”

“…Menthol may be added to tobacco to deliver a distinct oral sensation, as it imparts a characteristic cooling sensation via activation of transient receptor potential channel, subfamily M, member 8 (TRPM8) ion channels expressed in a population of thermosensory nerves (McKemy et al, 2002;Peier et al, 2002;Bautista et al, 2007). In turn, signaling downstream of TRPM8 can lead to analgesia through undefined mechanisms (Willis et al, 2011). In addition, menthol may produce analgesic/counterirritant effects through activation and desensitization of the nociceptive transient receptor potential channel, subfamily A, member 1 (TRPA1) channel (Macpherson et al, 2006;Karashima et al, 2007;Xiao et al, 2008) or by direct antagonism of the TRPA1 channel (Karashima et al, 2007;Xiao et al, 2008).…”

Antitussive Drugs—Past, Present, and Future

“…In mice, irritancy induced by a wide range of protussive substances was inhibited by menthol, an effect that was antagonized by the TRPM8 antagonist AMTB (Willis et al, 2011). Recent evidence indicates that the antitussive activity of menthol may reside in the activation of nasal, as opposed to pulmonary sensory afferents (Plevkova et al, 2013), inferring that menthol inhibits cough by a central "gating" mechanism rather than any local antitussive activity.…”