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Menthol decreases oral nicotine aversion in C57BL/6 mice through a TRPM8-dependent mechanism
  1. Lu Fan1,
  2. Shrilatha Balakrishna1,
  3. Sairam V Jabba2,
  4. Pamela E Bonner2,
  5. Seth R Taylor1,
  6. Marina R Picciotto1,
  7. Sven-Eric Jordt1,2
  1. 1Department of Psychiatry, Yale Tobacco Center of Regulatory Science (TCORS), Yale School of Medicine, New Haven, Connecticut, USA
  2. 2Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina, USA
  1. Correspondence to Dr Sven-Eric Jordt, Department of Anesthesiology, Duke University School of Medicine, Box 3094 MS27, Durham, NC 27710-3094, USA; sven.jordt{at}


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 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.

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.

  • Addiction
  • Nicotine
  • Non-cigarette tobacco products
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  • Correction notice This article has been corrected since it was published Online First. In the Abstract, ‘50% or 100 mg/mL’ has been corrected to ‘50 or 100 mg/mL’ in the sentence ‘When presented with a highly aversive concentration of nicotine (200 mg/mL), mice preferred solutions with 50 or 100 mg/mL menthol added…’.

  • Contributors S-EJ and MRP conceived of the study. LF, SB, SVJ, PEB and SRT performed experiments. LF, SB, SVJ, MRP and S-EJ contributed to data analysis; interpretation of data; writing of the manuscript and review, revision and approval of the final article. S-EJ is guarantor of the study.

  • Funding This work was supported by the National Institute on Drug Abuse and the Center for Tobacco Products of the US Food and Drug Administration under Award Numbers P50DA036151 (Yale Tobacco Center of Regulatory Science, TCORS).

  • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the views of the NIH or the FDA.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Data are available for download on request from the Duke Department of Anesthesiology's primary data server.

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