Role of High Omega-6 Diet as a Risk Factor for Pain Through Increased TRPV1 and TRPA1 Activity

摘要 医生建议对心血管疾病进行饮食干预， 糖尿病和许多自身免疫性疾病；然而，对其作用的认识存在很大差距 饮食是慢性疼痛的危险因素或潜在的治疗方法。疼痛的管理仍然是一个重要的 医学上的问题，部分原因是对脑出血的生理机制认识不完全。 伤害性刺激的传导和处理。此外，目前的止痛药往往受到以下限制 疗效不完全，不可接受的副作用或依赖的风险。这两个国家的新发现 治疗和预防慢性疼痛是必不可少的，并调查饮食与 而疼痛使新疗法的潜在开发以及对疼痛的更好理解 持续性疼痛的机制。 多项研究表明，亚油酸(LA)或花生四烯酸的氧化代谢产物 酸(AA)在激活瞬时受体电位(Trp)通道方面具有很强的生物学作用， 包括在伤害性神经元上表达的TRPV1和TRPA1。因为洛杉矶和AA是 必需的omega-6多不饱和脂肪酸(PUFA)，它们的生理水平是饮食的函数 入口处。本申请中提供的初步数据表明，喂食15周高位的小鼠 Omega-6饮食表现出基础热和机械伤害性阈值的变化和增加 对有害刺激的反应。然而，在知识方面仍然存在很大的差距，因为 目前尚不清楚饮食中的omega-6脂肪摄入对疼痛的调节作用。基于最近的研究和我们的 初步数据，我们建议检验以下中心假设：增加膳食omega-6多不饱和脂肪酸会导致 通过增加TRPV1和TRPA1来增加热痛觉过敏和机械性痛觉异常 活动。 饮食诱导的TRPV1和TRPA1活性升高可能是 多种慢性疼痛状况，并在从急性疼痛向慢性疼痛的过渡中发挥作用。这个 以下目标将检验这一假设： 具体目标1：评估15周高omega-6饮食后细胞脂质成分的变化 确定脂质在热和机械伤害性感受中的作用。 具体目标2：研究TRPV1和TRPA1在增加热量和机械性能中的作用 高omega-6饮食后的伤害感。 具体目标#3：确定高脂饮食是否以性别特有的方式改变伤害性感受。 这项研究在确定环境因素的原理和潜力方面是创新的， 预感并有可能预测疼痛反应。该项目还可能带来新的治疗方法 治疗和预防慢性疼痛状况的方法。此外，这些技术和 研究方法为我作为一名学术内科科学家的职业生涯提供了理想的培训工具。

Abstract Physicians recommend dietary interventions for management of cardiovascular disease, diabetes and many autoimmune diseases; however, there is a large gap in knowledge on the role of diet as a risk factor or potential therapy for chronic pain. Management of pain remains a substantial medical problem, in part, because of an incomplete understanding of the physiologic mechanisms for transduction and processing of noxious stimuli. Moreover, current analgesics are often limited by incomplete efficacy, unacceptable side effects or risk of dependency. New discoveries for both the treatment and prevention of chronic pain are essential, and investigating the relationship between diet and pain allows for the potential development of new therapies along with a better understanding of the mechanisms of persistent pain. Multiple studies have demonstrated that oxidized metabolites of linoleic acid (LA) or arachidonic acid (AA) have potent biological actions in activating transient receptor potential (TRP) channels, including TRPV1 and TRPA1, that are expressed on nociceptive neurons. Since LA and AA are essential omega-6 polyunsaturated fatty acids (PUFA), their physiologic levels are a function of dietary intake. Preliminary data presented in this application demonstrate that mice fed a 15-week high omega-6 diet exhibit changes in basal thermal and mechanical nociceptive thresholds and increased responses to noxious stimuli. However, there is still a large gap in knowledge as the mechanisms by which dietary omega-6 lipid intake modulate pain is not understood. Based on recent studies and our preliminary data, we propose to test the central hypothesis that increased dietary omega-6 PUFA leads to increased thermal hyperalgesia and mechanical allodynia via increased TRPV1 and TRPA1 activities. Diet-induced increased TRPV1 and TRPA1 activity could be a common mechanism among multiple chronic pain conditions and play a role in the transition from acute to chronic pain. The following aims will test the hypothesis: Specific Aim #1: Assess cellular lipid composition change following a 15-week high omega-6 diet and determine the role of the lipids in thermal and mechanical nociception. Specific Aims #2: Investigate the role of TRPV1 and TRPA1 in increased thermal and mechanical nociception following a high omega-6 diet. Specific Aim #3: Determine whether high lipid diet alters nociception in a sex-specific manner. This study is innovative in its rationale and potential for identifying an environmental factor that could predispose and possibly predict pain response. This project may also lead to novel therapeutic approaches for treatment and prevention of chronic pain conditions. Moreover, the techniques and research methods provide an ideal training vehicle for my career as an academic physician-scientist.