title: Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism.
abstract: 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.
  
  
  
  The two-bottle choice drinking assay was used to characterise 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shrilatha
authors.initials: S
authors.lastname: Balakrishna
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Sairam V
authors.initials: SV
authors.lastname: Jabba
authors.affiliation: Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Pamela E
authors.initials: PE
authors.lastname: Bonner
authors.affiliation: Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Seth R
authors.initials: SR
authors.lastname: Taylor
authors.affiliation: Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA.
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.affiliation: Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA.|Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA.
authors.forename: Sven-Eric
authors.initials: SE
authors.lastname: Jordt
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D008610:Menthol / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage / Q000633:toxicity*; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000633:toxicity*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D014030:Tobacco, Smokeless / Q000633:toxicity
chemical_list: D018722:Nicotinic Agonists; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; D008610:Menthol; D009538:Nicotine
keywords: Addiction; Nicotine; Non-cigarette tobacco products