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.
Highlights
While the overall rate of cigarette smoking has decreased in the United States and other markets, the proportion of smokers consuming mentholated cigarettes has steadily increased [1]
The rate of menthol cigarette smokers is especially high among beginning smokers, with >50% of initiating smokers reporting the use of menthol cigarettes [1,2,3]
The current study was designed to extend our earlier findings, focusing on the actions of Lmenthol, the menthol isomer added to cigarettes, on the murine respiratory irritant response to individual smoke irritants and to cigarette smoke, and on a critical marker of nicotine exposure, cotinine
Summary
While the overall rate of cigarette smoking has decreased in the United States and other markets, the proportion of smokers consuming mentholated cigarettes has steadily increased [1]. The primary response is a change in breathing pattern, termed braking, which is characterized by a cessation of early expiratory airflow due to glottal closure [9,10]. This braking leads to a diminished breathing frequency which forms the basis for the murine sensory irritation bioassay [11]. Respiratory chemosensory responses are thought to be protective either by causing noxious sensations (e.g. burning, cough) and initiating avoidance behavior, and/or by altering the rate of absorption of airborne materials into airway epithelium or the bloodstream. Since the effects of menthol on first ever smoking cannot be examined in humans these studies relied on a well characterized mouse model [10,15]
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