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

项目摘要 薄荷醇是一种从薄荷中提取的降温萜类物质，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，薄荷醇尤其受欢迎 吸烟者以及不成比例地受到慢性阻塞性肺病、肺癌和 高血压。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。最近，有两个 感觉薄荷醇受体被鉴定为：TRPM8，冷/薄荷醇受体，和TRPA1，反应性 刺激性受体。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，吸入薄荷醇可有效抑制呼吸道刺激反应。 小鼠体内的丙烯醛蒸气。吸入薄荷醇香烟烟雾的小鼠表现出更高的血清水平 尼古丁代谢物可替宁比暴露在非薄荷醇烟雾中的小鼠更少，这表明 增加对尼古丁的接触。在电生理和荧光成像实验中，我们展示了 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 抗刺激剂，通过相互作用阻断感觉神经元对吸入有毒化学物质的反应 通过薄荷醇受体TRPA1或TRPM8，以及2)作为烟草添加剂，薄荷醇促进吸烟 吸入通过抑制神经元刺激性受体信号，从而加速尼古丁 依赖和肺部疾病。 在这项申请中提出的研究将使用生理、生化、分子和行为 方法：目标1。)明确TRPA1和TRPM8在薄荷醇诱导的急性脑缺血抑制中的作用 呼吸道刺激。目标2。)考察薄荷醇及其相关物质的药理作用 关于刺激物诱导的感觉神经元激活的化合物。目标3。)确定薄荷脑的作用 吸入治疗吸烟引起的肺部炎症和气肿。 我们提议的研究将提供对呼吸道刺激和神经机制的新见解 重塑，并为将薄荷醇作为烟草添加剂的监管努力确定科学基础。

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.