The Role of Oxidized Linoleic Acid Metabolites in NGF Induced Persistent Pain

描述（由申请人提供）：慢性疼痛的治疗是一个主要的卫生保健问题，部分原因是对持续性疼痛机制的不完全理解。现有的慢性疼痛治疗方法通常受到疗效差、副作用或依赖风险的限制，因此对慢性疼痛分子机制的基础研究对于开发更有效的镇痛药至关重要。 神经生长因子 (NGF) 是一种神经营养蛋白，在炎症条件下释放并调节伤害性或疼痛信号的传递。 NGF 已被证明能够使瞬时受体电位香草酸 1 (TRPV1) 急剧敏化，TRPV1 是一种在伤害性传入神经元主要亚群上表达的配体门控离子通道。内源性 NGF 在几种慢性疼痛状况下会升高，健康人单次施用 NGF 会产生持续长达 4-7 周的长期疼痛状态。尽管 NGF 和疼痛之间的联系已得到广泛认可，但对介导持续性疼痛的机制的理解仍存在差距。大多数临床前 NGF 研究重点关注 NGF 的急性效应（数秒至数小时），而 NGF 持续效应的机制仍不清楚。 为了实现这一目标，我们开发了一种 NGF 诱导的持续性热异常性疼痛（伤害性阈值降低）的啮齿动物模型，并证明 TRPV1 的拮抗作用能够在 NGF 从动物体内消除后很长时间内立即逆转异常性疼痛。最近的初步研究表明，内源性氧化脂质激动剂（包括氧化亚油酸代谢物（OLAM））对 TRPV1 的持续激活可能是 NGF 给药后导致持续、长期伤害性状态的外周机制。因此，该提案将检验以下中心假设：NGF 通过增加 TRPV1 通道的活性和增加内源性氧化脂质 TRPV1 激动剂（包括 OLAM）的产生而引起持续性热异常性疼痛。以下目标将检验这一假设： 具体目标#1：确定大鼠在持续性 NGF 诱导的热异常性疼痛期间 NGF 诱导的 TRPV1 活性变化。具体目标#2：确定 NGF 对氧化脂质（包括 OLAM）水平的影响，以及在持续 NGF 诱导的热异常性疼痛期间大鼠体内 TRPV1 的激活。 拟议的研究测试了一个创新且重要的假设，并提供了一种多学科的方法来发展我作为疼痛药理学独立研究者的职业生涯。

DESCRIPTION (provided by applicant): The management of chronic pain is a major health care problem due, in part, to an incomplete understanding of persistent pain mechanisms. Available chronic pain treatments are often limited by poor efficacy, side effects, or risks of dependency, therefore fundamental research into molecular mechanisms of chronic pain are critical in order to develop more efficacious analgesics. Nerve growth factor (NGF) is a neurotrophin that is released under inflammatory conditions and modulates the transmission of nociceptive or pain signals. NGF has been demonstrated to acutely sensitize transient receptor potential vanilloid 1 (TRPV1), a ligand gated ion channel expressed on a major subpopulation of nociceptive afferent neurons. Endogenous NGF is elevated in several chronic pain conditions, and a single administration of NGF to healthy humans produced a prolonged pain state that persisted up to 4-7 weeks. Although the link between NGF and pain is well recognized, there is a gap in understanding of the mechanisms mediating persistent pain. The majority of preclinical NGF studies focus on the acute effects (seconds to hours) of NGF, while the mechanisms underlying persistent NGF effects remain unknown. Towards this objective, we have developed a rodent model of NGF-induced persistent thermal allodynia (a reduced nociceptive threshold) and demonstrated that antagonism of TRPV1 was able to immediately reverse allodynia at a time point long after the NGF was physically eliminated from the animals. More recent preliminary studies suggest that persistent activation of TRPV1 by endogenous oxidized lipid agonists, including oxidized linoleic acid metabolites (OLAMs), may be a peripheral mechanism contributing towards a persistent, long-term nociceptive state after NGF administration. Therefore, this proposal will test the central hypothesis that NGF causes persistent thermal allodynia via increased activities of TRPV1 channels and increased production of endogenous oxidized lipid TRPV1 agonists, including OLAMs. The following aims will test this hypothesis: Specific Aim #1: Determine NGF-induced changes in TRPV1 activity in rats during persistent NGF- induced thermal allodynia. Specific Aim #2: Define the effect of NGF on levels of oxidized lipids, including OLAMs, and their activation of TRPV1 in rats during persistent NGF-induced thermal allodynia. The proposed studies test an innovative and significant hypothesis and provide a multidisciplinary approach to develop my career as an independent investigator in pain pharmacology.