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

薄荷醇抗刺激：分子靶标及其在气道疾病中的作用

基本信息

批准号：
8209236
负责人：
SVEN-ERIC JORDT
金额：
$ 40.42万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8209236
关键词：
Acrolein Acute Address Affect Afferent Neurons Analgesics Asthma Behavioral Biochemical Biological Factors Breathing C Fiber Chemicals Chronic Chronic Obstructive Airway Disease Cigarette Cigarette smoke-induced emphysema Cotinine Coughing Disease Exposure to Food Gene Family Goals Government Hypertension Hypesthesia Image Individual Inflammation Inflammatory Inhalation Exposure Ion Channel Irritants Lung Inflammation Lung diseases Malignant neoplasm of lung Mediating Mentha piperita Menthol Minority Modeling Molecular Molecular Target Mouse Strains Mus Nerve Fibers Neurons Neuropeptides Nicotine Nicotine Dependence Nociception Outcome Pain Pharmaceutical Preparations Physiological Pneumonia Population Process Protein Isoforms Publishing Receptor Signaling Research Respiratory System Role Sensory Serum Smoke Smoker Smoking Symptoms System TRPA1 Channel Terpenes Testing Therapeutic Time Tobacco Tobacco smoke Work afferent nerve base cigarette smoking insight irritation mouse model receptor research study respiratory respiratory reflex response smoke inhalation vapor

项目摘要

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.

项目概要薄荷醇是从薄荷中提取的具有清凉功效的萜烯，广泛用于治疗咳嗽、呼吸道刺激和疼痛。薄荷醇作为卷烟添加剂特别受初学者欢迎吸烟者和少数民族人群受慢性阻塞性肺病、肺癌和高血压。目前尚不清楚薄荷醇是否通过以下方式导致这些疾病：抑制化学感应神经元介导的呼吸道刺激反应。最近，两鉴定出感觉薄荷醇受体：TRPM8（冷/薄荷醇受体）和 TRPA1（反应性受体）刺激受体。 TRPA1 被烟草烟雾中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的含量高于暴露于非薄荷醇烟雾的小鼠，这表明增加接触尼古丁。在电生理学和荧光成像实验中，我们表明薄荷醇抑制丙烯醛激活的 TRPA1 通道。我们假设： 1.) 薄荷醇充当抗刺激，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与薄荷醇受体 TRPA1 或 TRPM8 结合，以及 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来吸入，从而加速尼古丁的产生依赖性和肺部疾病。本申请中提出的研究将使用生理学、生化、分子和行为学目标 1.) 定义 TRPA1 和 TRPM8 在薄荷醇诱导的急性抑制中的作用呼吸道刺激。目标 2.) 检查薄荷醇和薄荷醇相关药物的药理作用化合物对刺激引起的感觉神经元激活的影响。目标 3.) 确定薄荷醇的作用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气道刺激的神经元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基础。