Menthol, the cooling terpene derived from peppermint, is widely used for the treatment of cough, respiratory irritation and pain. As a cigarette additive menthol is especially popular with beginning smokers and in minority populations disproportionally affected by COPD, lung cancer and hypertension. It is currently unclear whether menthol contributes to these disease conditions through inhibition of the respiratory irritation response mediated by chemosensory neurons. Recently, two sensory menthol receptors were identified: TRPM8, the cold/menthol receptor, and TRPA1, a reactive irritant receptor. TRPA1 is activated by acrolein and other irritants contained in tobacco smoke. Our preliminary studies show that inhalation of menthol potently inhibits the respiratory irritation response to acrolein vapor in mice. Mice inhaling smoke from mentholated cigarettes showed higher serum levels of the nicotine metabolite, cotinine, than mice exposed to non-mentholated smoke, suggesting increased exposure to nicotine. In electrophysiological and fluorescent imaging experiments we show that menthol inhibits acrolein-activated TRPA1 channels. We hypothesize that: 1.) Menthol acts as a counterirritant, blocking sensory neuronal responses to inhaled noxious chemicals through interaction with the menthol receptors TRPA1 or TRPM8, and 2) As a tobacco additive, menthol facilitates smoke inhalation through inhibition of neuronal irritant receptor signalling, thereby accelerating nicotine dependence and lung disease. The studies proposed in this application will use physiological, biochemical, molecular and behavioral approaches to:
Aim 1.) Define the roles of TRPA1 and TRPM8 in menthol-induced inhibition of acute respiratory irritation.
Aim 2.) Examine the pharmacological effects of menthol and menthol-related compounds on irritant-induced activation of sensory neurons.
Aim 3.) Determine the effects of menthol inhalation on smoking-induced lung inflammation and emhysema. Our proposed research will provide new insights into neuronal mechanisms of airway irritation and remodeling, and define a scientific basis for regulatory efforts targeting menthol as a tobacco additive.

Public Health Relevance

/ Relevance The natural product menthol is contained in medications against cold symptoms and pain, in food and in cigarettes. This application aims to reveal how menthol reduces irritation, and if menthol causes more severe smoking-related disease. Our work may aid the government in determining whether to regulate menthol as a cigarette additive, and may reveal new treatments for cough and pain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL105635-02
Application #
8209236
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Punturieri, Antonello
Project Start
2011-01-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
2
Fiscal Year
2012
Total Cost
$404,160
Indirect Cost
$104,409
Name
Yale University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Liu, Boyi; Fan, Lu; Balakrishna, Shrilatha et al. (2013) TRPM8 is the principal mediator of menthol-induced analgesia of acute and inflammatory pain. Pain 154:2169-77
Willis, Daniel N; Liu, Boyi; Ha, Michael A et al. (2011) Menthol attenuates respiratory irritation responses to multiple cigarette smoke irritants. FASEB J 25:4434-44