Role of Oxidized Linoleic Acid Metabolites in Pain

氧化亚油酸代谢物在疼痛中的作用

• 批准号: 8144840
• 负责人: Kenneth M Hargreaves
• 金额: $ 36.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144840
• 关键词: Address; Afferent Neurons; Agonist; Analgesics; Arachidonic Acids; Biopsy; Capsaicin; Chemicals; Chili Pepper; Data; Family; Gated Ion Channel; Gene Deletion; Generations; Heating; Hyperalgesia; Inflammation; Inflammatory; Lead; Ligands; Linoleic Acids; Lipids; Lipoxygenase; Malignant Neoplasms; Medical; Modeling; Neuropathy; Nociceptors; Pain; Pain management; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phospholipase D; Physiologic Thermoregulation; Physiological; Regulation; Research; Role; Skin; Stimulus; Thermal Hyperalgesias; allodynia; base; cellular transduction; detector; drug development; fundamental research; improved; in vivo; innovation; member; novel; novel strategies; pain receptor; pre-clinical; public health relevance; receptor

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.

描述（由申请人提供）：疼痛的治疗仍然是一个主要的医学问题，其至少部分归因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均证明 TRPV1（瞬时受体电位亚型 V1）在炎性热痛觉过敏和体温调节中发挥着关键作用，并且该受体在很大一部分痛觉感觉神经元（称为伤害感受器）中表达。有趣的是，TRPV1 内源性激活的精确机制仍然未知。在此应用中，我们将评估 TRPV1 活性受内源性氧化亚油酸代谢物 (OLAM) 调节的创新假设。我们的初步数据表明，热量通过促进该通道的热响应性，引起亚油酸代谢物的释放，这些代谢物构成了生理相关 TRPV1 激动剂的新家族。根据之前的研究和我们自己的结果，我们提出了一个中心假设，即某些外周刺激会触发调节 TRPV1 活性的 OLAM 的释放。具体目标 1：确定培养的感觉神经元中 OLAM 诱导的 TRPV1 激活产生所涉及的关键酶途径。具体目标 2：评估对照与发炎皮肤活检中调节 OLAM 诱导的 TRPV1 活性的关键外周酶通路的生理相关性。具体目标 3：评估体内调节炎症热痛觉过敏/异常性疼痛的关键外周酶通路的生理相关性。这一新的假设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含镇痛药物开发的新靶点。此外，OLAM对TRPV1活性调节的发现为疼痛转导提供了一种新颖且以前未知的机制，可能会促进对有害刺激的细胞转导的基础研究，以及从炎症到神经病性疾病再到癌症相关的临床前疼痛模型的研究。疼痛。 公共卫生相关性：增加对疼痛机制的了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。在此应用中，我们建议研究内源性氧化亚油酸代谢物 (OLAM) 在激活一种重要的疼痛受体 TRPV1（瞬时受体电位亚型 V1）中的作用。拟议的研究可能具有相当大的医学意义，因为抑制 OLAM 合成或功能的药物可以作为新型镇痛药。