The Capsaicin Receptor TRPV1, a Novel Target for Omega-3 Fatty Acids

描述（由申请人提供）：辣椒素受体或瞬时受体潜在香兰素亚型1 （TRPV1）是一种非选择性阳离子通道，在炎症性疼痛信号传导和血管生理中起关键作用。TRPV1是炎性疼痛的分子传感器，其激活的多模态特性使神经元能够整合各种有害刺激，如热、低pH和炎性类二十烷。尽管TRPV1与痛觉有关，但该蛋白也通过诱导神经肽释放和血管舒张而作为血管生理学的重要调节因子。因此，低内效的部分激动剂可以作为trpv1介导的疼痛的阻滞剂，并促进神经肽的释放，从而实现血管舒张和积极的血管作用。有趣的是，omega-3多不饱和脂肪酸（n-3 PUFAs）似乎具有明显的镇痛特性，对血管有积极作用，并与预防心脏疾病有关，如动脉粥样硬化、心律失常和各种炎症和自身免疫性疾病。我们最近的数据表明，n-3脂肪酸选择性地上调和下调TRPV1。本提案的长期目标是确定n-3 PUFAs的心血管益处和镇痛特性是否可能部分通过与TRPV1的相互作用引起。通过了解n-3 PUFAs和TRPV1之间的相互作用，可能会开发出治疗炎症性疼痛和某些心血管疾病的新疗法。本研究将确定n-3 PUFAs如何调节TRPV1以及该机制在体内的生理相关性。来自表达TRPV1通道的单细胞的电生理记录将确定n-3 PUFAs调节TRPV1的分子机制。n-3 PUFAs的潜在心血管益处将通过测量trpv1介导的神经肽从感觉神经的释放来研究。n-3 PUFAs的镇痛特性将通过辣椒素引起的小鼠疼痛相关行为测试进行测试。这项拟议的研究将进一步加深我们对n- 3 PUFAs作为治疗心脏病和炎症性疼痛的方法的理解，这两个主要的公共卫生问题在我国通常是相互伴随的。由于麻醉药和非甾体抗炎药的成瘾性、毒性和药物-药物相互作用特性，治疗疼痛的替代品或佐剂是一个高度优先考虑的问题。因此，TRPV1可能作为n-3 PUFAs的新分子靶点，为心血管疾病和疼痛的治疗提供了新的途径。

DESCRIPTION (provided by applicant): The capsaicin receptor or transient receptor potential vanilloid subtype 1 (TRPV1) is a non-selective cation channel that plays a critical role in inflammatory pain signaling and vascular physiology. TRPV1 is a molecular sensor of inflammatory pain and its multimodal properties for activation enable neuronal integration of a variety of noxious stimuli such as heat, low pH and inflammatory eicosanoids. Although TRPV1 is implicated in pain sensation, this protein also serves as an imprtant regulator of vascular physiology by inducing neuropeptide release and consequently, vasodilation. Thus partial agonists with low intrisic efficacy may serve as blockers of TRPV1-mediated pain, as well as promote the release of neuropeptides to allow vasodilation and positive vascular effects. Interestingly, omega-3 polyunsaturated fatty acids (n-3 PUFAs) appear to have pronounced analgesic properties, positive vascular effects, and are implicated in the prevention of cardiac diseases, such as atherosclerosis, cardiac arrhythmias and various inflammatory and autoimmune conditions. Our recent data suggests a selective up- and down-regulation of TRPV1 by n-3 fatty acids. The long-term goal of this proposal is to determine whether the cardiovascular benefits and analgesic properties of n-3 PUFAs may be in part elicited via an interaction with TRPV1. By understanding the interactions between n-3 PUFAs and TRPV1, novel therapies for inflamatory pain and certain cardivascular diseases may develop. This study will determine how n-3 PUFAs regulate TRPV1 and the physiological relevance of this mechanism in vivo. Electrophysiological recordings from single cells expressing the TRPV1 channel will determine the molecular mechanism for TRPV1 modulation by n-3 PUFAs. The potential cardiovascular benefits of n-3 PUFAs will be studied by measuring TRPV1-mediated release of neuropeptides from sensory nerves. The analgesic properties of n-3 PUFAs will be tested with a capsaicin-evoked pain-related behavior test in mice. The proposed study will further our understanding of n- 3 PUFAs as a therapeutic approach to cardiac diseases and inflammatory pain, two major public health problems in our nation which usually accompany each other. Alternatives or adjuvants to narcotics and non- steroidal anti-inflammatory drugs for the treatment of pain is a high priority due to the addictive, toxic, and drug-drug interaction properties of these medicines. Thus, TRPV1 may serve as a new molecular target for n-3 PUFAs and provide a novel approach in the treatment of cardivascular diseases and pain,