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, ? ? ?