Role of Oxidized Linoleic Acid Metabolites in Pain

描述（由申请人提供）：疼痛的管理仍然是一个主要的医学问题，这至少部分是由于对有害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证明了TRPV 1（瞬时受体电位亚型V1）在炎症性热痛觉过敏和体温调节中的关键作用，该受体在相当大比例的疼痛感觉神经元（称为伤害感受器）中表达。有趣的是，TRPV 1内源性激活的确切机制仍然未知。在本申请中，我们将评估TRPV 1活性受内源性氧化亚油酸代谢物（OLAMs）调节的创新假设。我们的初步数据表明，热引起亚油酸代谢产物的释放，包括一个新的家庭的生理相关的TRPV 1激动剂通过促进该通道的热响应性。基于以前的研究和我们自己的结果，我们提出了一个中心假设，即某些外周刺激触发释放调节TRPV 1活动的OLAMs。具体目的1：确定在培养的感觉神经元中参与OLAM诱导的TRPV 1激活的产生的关键酶途径。具体目标二：在对照与炎症皮肤活检中评价调节OLAM诱导的TRPV 1活性的关键外周酶途径的生理相关性。具体目标3：评价关键外周酶途径在体内调节炎性热痛觉过敏/异常性疼痛的生理相关性。这种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镇痛药物开发的新靶点。此外，OLAM调节TRPV 1活性的发现为疼痛转导提供了一种新的和以前未知的机制，这可能促进对有害刺激的细胞转导的基础研究以及对从炎症到神经性病症到癌症相关疼痛的临床前疼痛模型的研究。 公共卫生相关性：增加对疼痛机制的理解可能会通过确定开发镇痛药物的新方法来改善疼痛管理。在本申请中，我们建议研究内源性氧化亚油酸代谢物（OLAM）在激活一种重要疼痛受体（称为TRPV 1（瞬时受体电位亚型V1））中的作用。由于抑制OLAM合成或功能的药物可能作为新型镇痛药，因此拟议的研究可能具有相当大的医学意义。

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. PUBLIC HEALTH RELEVANCE: Increased understanding of pain mechanisms may lead to improved pain management by identifying new approaches for developing analgesic drugs. In this application, we propose to study the role of endogenous oxidized linoleic acid metabolites (OLAMs) in activating an important pain receptor, called TRPV1 (transient receptor potential subtype V1). The proposed studies may have considerable medical significance since drugs that inhibit OLAM synthesis or function may serve as novel analgesics.