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

描述（由申请人提供）：慢性疼痛的管理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往往受到疗效差、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）是一种在炎症条件下释放的神经营养因子，并调节伤害或疼痛信号的传递。神经生长因子已被证明对瞬时受体电位香草样蛋白1 （TRPV1）具有急性敏感性，TRPV1是一种配体门控离子通道，在伤害性传入神经元的主要亚群上表达。内源性NGF在几种慢性疼痛状态下升高，健康人群单次服用NGF可产生持续4-7周的疼痛状态。尽管神经生长因子与疼痛之间的联系已得到充分认识，但对介导持续性疼痛的机制的理解仍存在空白。大多数临床前NGF研究集中在NGF的急性作用（秒至小时），而NGF持续作用的机制尚不清楚。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，并证明了TRPV1的拮抗能够在NGF从动物体内消除后很长一段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（OLAMs））对TRPV1的持续激活可能是NGF给药后导致持续长期伤害状态的外周机制。因此，本研究将验证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OLAMs）的产生导致持续性热异常性疼痛的中心假设。以下目标将验证这一假设：具体目标1：确定NGF诱导的持续热异常性疼痛大鼠中TRPV1活性的变化。特定目标#2：确定NGF对氧化脂质水平的影响，包括OLAMs，以及它们在持续NGF诱导的热异常性痛大鼠中TRPV1的激活。提议的研究测试了一个创新的和重要的假设，并提供了一个多学科的方法来发展我的职业生涯作为一个独立的研究者在疼痛药理学。

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.