Role of Oxidized Linoleic Acid Metabolites in Pain

描述(申请人提供)：疼痛的管理仍然是一个主要的医学问题，至少部分是由于对伤害性刺激转导的生理机制的不完全理解。药理学和基因缺失研究都表明，TRPV1(瞬时受体电位亚型V1)在炎性热痛觉过敏和体温调节中起关键作用，该受体在相当大比例的痛觉感觉神经元中表达，称为伤害性感受器。有趣的是，TRPV1内源性激活的确切机制(S)仍不清楚。在这个应用中，我们将评估创新的假设，即TRPV1的活性由内源性氧化亚油酸代谢产物(OLAM)调节。我们的初步数据表明，热引起亚油酸代谢物的释放，亚油酸代谢物组成了一个新的生理相关的TRPV1激动剂家族，有助于该通道的热响应。基于前人的研究和我们自己的结果，我们提出了一个中心假说，即某些外周刺激会触发调节TRPV1活性的OLAM的释放。具体目的1：确定OLAM诱导培养的感觉神经元产生TRPV1的关键酶途径(S)。具体目的2：评估调节OLAM诱导的TRPV1活性的关键外周酶途径(S)在对照组和炎症皮肤活检组织中的生理学相关性。具体目的3：评价外周关键酶途径(S)在体内调节炎性热痛敏/痛敏的生理学意义。这一新的假说可能具有相当大的医学意义，因为抑制OLAM合成或功能的机制可能包括止痛药开发的新靶点。此外，OLAM对TRPV1活性调控的发现为疼痛转导提供了一种新的和以前未知的机制，可能会促进伤害性刺激的细胞转导的基础研究，以及从炎症到神经病变到癌症相关疼痛的临床前疼痛模型的研究。

DESCRIPTION (provided by applicant): The management of pain remains a major medical problem that is due, at least in part, to an incomplete understanding of the physiologic mechanisms for transduction of noxious stimuli. Both pharmacological and gene deletion studies have demonstrated a pivotal role for TRPV1 (transient receptor potential subtype V1) in inflammatory heat hyperalgesia and thermoregulation and this receptor is expressed in a significant proportion of pain-sensing sensory neurons, termed nociceptors. Interestingly, the precise mechanism(s) for the endogenous activation of TRPV1 remains unknown. In this application, we will evaluate the innovative hypothesis that TRPV1 activities are regulated by endogenous oxidized linoleic acid metabolites (OLAMs). Our preliminary data demonstrate that heat evokes the release of linoleic acid metabolites that comprise a new family of physiologically relevant TRPV1 agonists by contributing to the heat responsiveness of this channel. Based upon previous studies and our own results, we propose the central hypothesis that certain peripheral stimuli trigger the release of OLAMs that regulate TRPV1 activities. Specific Aim 1: Determine the key enzymatic pathway(s) involved in the generation of OLAM- induced TRPV1 activation in cultured sensory neurons. Specific Aim 2: Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) regulating OLAM-induced TRPV1 activities in control vs inflamed skin biopsies. Specific Aim 3: Evaluate the physiologic relevance of key peripheral enzymatic pathway(s) for regulating inflammatory thermal hyperalgesia/allodynia in vivo. This novel hypothesis may have considerable medical significance since mechanisms inhibiting OLAM synthesis or function may comprise novel targets for analgesic drug development. In addition, the discovery of OLAM regulation of TRPV1 activities provides a novel and previously unknown mechanism for pain transduction that may promote fundamental research into cellular transduction of noxious stimuli as well as research on preclinical pain models ranging from inflammation to neuropathic conditions to cancer-related pain.