Counter-Irritation by Menthol: Molecular Targets and Role in Airway Disease

项目摘要 薄荷脑是一种从薄荷中提取的清凉萜烯，广泛用于治疗咳嗽， 呼吸道刺激和疼痛。作为香烟添加剂，薄荷醇特别受初 吸烟者和少数受COPD、肺癌和 高血压目前尚不清楚薄荷醇是否通过以下途径导致这些疾病 抑制由化学感觉神经元介导的呼吸刺激反应。最近有两 鉴定了感觉薄荷醇受体：TRPM 8，冷/薄荷醇受体，和TRPA 1，反应性受体。 刺激性受体TRPA 1被丙烯醛和烟草烟雾中的其他刺激物激活。我们 初步研究表明，吸入薄荷醇可有效抑制呼吸道刺激反应 丙烯醛蒸汽的反应吸入含薄荷香烟烟雾的小鼠血清中 尼古丁代谢物可替宁的含量比暴露于非薄荷醇烟雾的小鼠高，这表明 增加对尼古丁的接触。在电生理学和荧光成像实验中， 薄荷醇抑制丙烯醛激活的TRPA 1通道。我们假设：1.）门童作为一个 抗刺激剂，通过相互作用阻断感觉神经元对吸入有害化学物质的反应 与薄荷醇受体TRPA 1或TRPM 8，和2）作为烟草添加剂，薄荷醇促进吸烟 通过抑制神经元刺激受体信号传导吸入，从而加速尼古丁 依赖和肺病。 本申请中提出的研究将使用生理、生物化学、分子和行为 目标：1）。确定TRPA 1和TRPM 8在薄荷醇诱导的急性抑制中的作用。 呼吸道刺激。目标2）检查薄荷醇的药理作用和薄荷醇相关 化合物对刺激物诱导的感觉神经元活化的影响。目标3）确定薄荷醇的效果 吸入对吸烟引起的肺部炎症和水肿的影响。 我们提出的研究将为气道刺激的神经机制提供新的见解， 重塑，并为针对薄荷醇作为烟草添加剂的监管工作确定科学依据。

Project Summary 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.