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电位香草酸亚型1（TRPV 1）是一种非选择性阳离子通道，在炎症疼痛信号传导和血管生理学中起关键作用。TRPV 1是炎性疼痛的分子传感器，其激活的多模式特性使神经元能够整合各种有害刺激，如热、低pH和炎性类花生酸。虽然TRPV 1与疼痛感觉有关，但该蛋白质也通过诱导神经肽释放并因此导致血管舒张而充当血管生理学的重要调节剂。因此，具有低药效的部分激动剂可以作为TRPV 1介导的疼痛的阻断剂，以及促进神经肽的释放以允许血管舒张和积极的血管效应。有趣的是，ω-3多不饱和脂肪酸（n-3 PUFA）似乎具有显著的镇痛特性，积极的血管效应，并涉及预防心脏疾病，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，选择性上调和下调TRPV 1的n-3脂肪酸。该提案的长期目标是确定n-3 PUFA的心血管益处和镇痛特性是否可以部分通过与TRPV 1的相互作用引起。通过了解n-3 PUFAs和TRPV 1之间的相互作用，可能会开发用于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TRPV 1以及这种机制在体内的生理相关性。来自表达TRPV 1通道的单细胞的电生理记录将确定n-3 PUFA调节TRPV 1的分子机制。将通过测量TRPV 1介导的感觉神经释放神经肽来研究n-3 PUFA的潜在心血管益处。将在小鼠中用辣椒素诱发的疼痛相关行为测试来测试n-3 PUFA的镇痛特性。这项拟议的研究将进一步加深我们对n- 3 PUFA作为心脏病和炎性疼痛的治疗方法的理解，这是我国两个主要的公共卫生问题，通常相互伴随。用于治疗疼痛的麻醉剂和非甾体抗炎药的替代品或佐剂是高度优先的，这是由于这些药物的成瘾性、毒性和药物-药物相互作用性质。因此，TRPV 1可能作为n-3 PUFA的新的分子靶点，并提供了治疗心血管疾病和疼痛的新方法，

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,