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医疗保健问题，部分原因是对持续性疼痛机制的不完全理解。可用的慢性疼痛治疗通常受到疗效差、副作用或依赖性风险的限制，因此对慢性疼痛的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）是一种神经营养因子，在炎症条件下释放并调节伤害性或疼痛信号的传递。已证明NGF急性致敏瞬时受体电位香草酸1（TRPV 1），TRPV 1是在伤害性传入神经元的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中升高，并且对健康人单次施用NGF产生持续长达4-7周的长期疼痛状态。虽然神经生长因子和疼痛之间的联系是公认的，有一个缺口的理解机制介导的持续性疼痛。大多数临床前研究集中在神经生长因子的急性效应（秒至小时），而持续神经生长因子的作用机制仍然未知。 为此，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TRPV 1的拮抗作用能够在NGF从动物体内物理消除后很长时间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）的持续激活TRPV 1，可能是一种外周机制，有助于持续的，长期的伤害性状态后，神经生长因子管理。因此，该提议将检验中心假设，即NGF通过增加TRPV 1通道的活性和增加内源性氧化脂质TRPV 1激动剂（包括OLAMs）的产生而引起持续性热异常性疼痛。具体目标#1：确定持续性NGF诱导的热异常性疼痛期间大鼠中NGF诱导的TRPV 1活性变化。具体目标#2：确定在持续性NGF诱导的热异常性疼痛期间，NGF对大鼠氧化脂质（包括OLAMs）水平及其TRPV 1激活的影响。 拟议的研究测试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.