Counterirritation by Menthol: Molecular Targets and Role in Airway Disease

薄荷醇的抗刺激作用：分子靶标及其在气道疾病中的作用

基本信息

批准号：
8022797
负责人：
SVEN-ERIC JORDT
金额：
$ 44.64万
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/8022797
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 Pulmonary Emphysema 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

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.

描述（由申请人提供）：Menthol是衍生自薄荷的冷却萜烯，被广泛用于治疗咳嗽，呼吸刺激和疼痛。作为烟熏添加剂薄荷醇特别受吸烟者特别受欢迎，在受COPD，肺癌和高血压影响的少数群体中，少数群体受到了欢迎。目前尚不清楚薄荷醇是否通过抑制化学感应神经元介导的呼吸刺激反应来促进这些疾病。最近，鉴定了两个感觉薄荷醇受体：TRPM8，冷/薄荷受体和TRPA1，一种反应性刺激受体。 TRPA1被丙烯醛激活，烟草烟中包含的其他刺激性。我们的初步研究表明，吸入薄荷醇可有效抑制小鼠对丙烯醛蒸气的呼吸刺激反应。吸入薄荷香烟吸入烟雾的小鼠比暴露于非注射烟雾的小鼠表现出更高的尼古丁代谢产物血清代谢产物水平，这表明暴露于尼古丁。在电生理和荧光成像实验中，我们表明薄荷醇抑制丙烯醛激活的TRPA1通道。 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 疾病。本应用中提出的研究将使用生理，生化，分子和行为方法来：AIM 1.）定义TRPA1和TRPM8在薄荷醇诱导的急性呼吸刺激抑制中的作用。目标2.）检查薄荷醇和薄荷醇相关化合物对刺激性诱导的感觉神经元激活的药理作用。目标3.）确定薄荷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和重塑的神经元机制提供新的见解，并为针对薄荷醇作为烟草添加剂的监管工作定义了科学基础。公共卫生相关性：天然产物薄荷醇包含在防寒和疼痛，食物和香烟中的药物中。该应用旨在揭示薄荷醇如何减少刺激，以及薄荷醇是否引起更严重的吸烟相关疾病。我们的工作可能有助于政府确定是否将薄荷醇调节为香烟添加剂，并可能揭示新的咳嗽和疼痛治疗方法。