title: Menthol attenuates respiratory irritation and elevates blood cotinine in cigarette smoke exposed mice.
abstract: Addition of menthol to cigarettes may be associated with increased initiation of smoking. The potential mechanisms underlying this association are not known. Menthol, likely due to its effects on cold-sensing peripheral sensory neurons, is known to inhibit the sensation of irritation elicited by respiratory irritants. However, it remains unclear whether menthol modulates cigarette smoke irritancy and nicotine absorption during initial exposures to cigarettes, thereby facilitating smoking initiation. Using plethysmography in a C57Bl/6J mouse model, we examined the effects of L-menthol, the menthol isomer added to cigarettes, on the respiratory sensory irritation response to primary smoke irritants (acrolein and cyclohexanone) and smoke of Kentucky reference 2R4 cigarettes. We also studied L-menthol's effect on blood levels of the nicotine metabolite, cotinine, immediately after exposure to cigarette smoke. L-menthol suppressed the irritation response to acrolein with an apparent IC₅₀ of 4 ppm. Suppression was observed even at acrolein levels well above those necessary to produce a maximal response. Cigarette smoke, at exposure levels of 10 mg/m³ or higher, caused an immediate and marked sensory irritation response in mice. This response was significantly suppressed by L-menthol even at smoke concentrations as high as 300 mg/m³. Counterirritation by L-menthol was abolished by treatment with a selective inhibitor of Transient Receptor Potential Melastatin 8 (TRPM8), the neuronal cold/menthol receptor. Inclusion of menthol in the cigarette smoke resulted in roughly a 1.5-fold increase in plasma cotinine levels over those observed in mice exposed to smoke without added menthol. These findings document that, L-menthol, through TRPM8, is a strong suppressor of respiratory irritation responses, even during highly noxious exposures to cigarette smoke or smoke irritants, and increases blood cotinine. Therefore, L-menthol, as a cigarette additive, may promote smoking initiation and nicotine addiction.
authors: Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
authors: Michael A
authors: MA
authors: Ha
authors: Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
authors: Gregory J
authors: GJ
authors: Smith
authors: Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
authors: Joseph A
authors: JA
authors: Cichocki
authors: Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, United States of America.
authors: Lu
authors: L
authors: Fan
authors: Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut, United States of America.
authors: Yi-Shiuan
authors: YS
authors: Liu
authors: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors: Ana I
authors: AI
authors: Caceres
authors: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, United States of America.
authors: Sven Eric
authors: SE
authors: Jordt
authors: Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America.
authors: John B
authors: JB
authors: Morris
mesh_terms: D000171:Acrolein / Q000008:administration & dosage; D000818:Animals; D003367:Cotinine / Q000097:blood*; D005260:Female; D007509:Irritants / Q000008:administration & dosage; D008610:Menthol / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D012119:Respiration / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D050053:TRPM Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors
chemical_list: D007509:Irritants; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; D000171:Acrolein; D003367:Cotinine