Counterirritation by Menthol: Molecular Targets and Role in Airway Disease

描述(申请人提供)：薄荷醇是一种从薄荷中提取的冷却萜类物质，广泛用于治疗咳嗽、呼吸道刺激和疼痛。作为一种香烟添加剂，薄荷醇在刚开始吸烟的人中特别受欢迎，在受COPD、肺癌和高血压影响不成比例的少数人群中尤其受欢迎。目前尚不清楚薄荷醇是否通过抑制化学感觉神经元介导的呼吸刺激反应而导致这些疾病。最近发现了两种感觉薄荷醇受体：TRPM8，冷/薄荷醇受体和TRPA1，反应性刺激受体。TRPA1被烟草烟雾中含有的丙烯醛和其他刺激物激活。我们的初步研究表明，吸入薄荷脑有效地抑制了小鼠对丙烯醛蒸气的呼吸道刺激反应。吸入薄荷醇香烟烟雾的小鼠血清尼古丁代谢物可替宁水平高于暴露在非薄荷醇香烟烟雾中的小鼠，这表明尼古丁的暴露增加。在电生理和荧光成像实验中，我们发现薄荷醇抑制丙烯醛激活的TRPA1通道。我们假设：1.)薄荷醇作为一种反刺激剂，通过与薄荷醇受体TRPA1或TRPM8相互作用，阻断感觉神经元对吸入有毒化学物质的反应，以及2)作为烟草添加剂，薄荷醇通过抑制神经元刺激受体信号促进烟雾吸入，从而加速尼古丁依赖和肺部疾病。本申请中提出的研究将使用生理、生化、分子和行为方法来：目标1。)明确TRPA1和TRPM8在薄荷醇诱导的抑制急性呼吸道刺激中的作用。目标2。)研究薄荷醇及其相关化合物对刺激物诱导的感觉神经元激活的药理作用。目标3。)确定薄荷脑吸入对吸烟引起的肺部炎症和肺气肿的影响。我们提出的研究将为呼吸道刺激和重塑的神经机制提供新的见解，并为将薄荷醇作为烟草添加剂的监管工作确定科学基础。 与公共健康相关：天然产品薄荷醇包含在治疗感冒症状和疼痛的药物、食品和香烟中。这项应用旨在揭示薄荷醇如何减少刺激性，以及薄荷醇是否会导致更严重的吸烟相关疾病。我们的工作可能会帮助政府决定是否将薄荷醇作为香烟添加剂进行监管，并可能揭示治疗咳嗽和疼痛的新疗法。

DESCRIPTION (provided by applicant): 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 emphysema. 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: 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.