title: 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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, USA.
authors: Daniel N
authors: DN
authors: Willis
authors: Boyi
authors: B
authors: Liu
authors: Michael A
authors: MA
authors: Ha
authors: Sven-Eric
authors: SE
authors: Jordt
authors: John B
authors: JB
authors: Morris
mesh_terms: D000171:Acrolein / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D003511:Cyclohexanols / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077591:Eucalyptol; D005260:Female; D007509:Irritants / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008610:Menthol / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D039821:Monoterpenes / Q000494:pharmacology; D012137:Respiratory System / Q000187:drug effects / Q000294:innervation; D011984:Sensory Receptor Cells / Q000187:drug effects; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects*; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics
chemical_list: D003511:Cyclohexanols; D007509:Irritants; D039821:Monoterpenes; D012906:Smoke; D000074025:TRPA1 Cation Channel; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D008610:Menthol; D000171:Acrolein; D003577:Cytochrome P-450 Enzyme System; D000077591:Eucalyptol