Resolution pathway of pain

描述(申请人提供)：3000多万美国人患有未缓解的慢性疼痛，这被认为是一种有其自身病理的疾病。目前的研究重点是疼痛是如何诱导的，但尚不清楚急性疼痛是如何自然缓解的。我们假设，局部主动前分解过程的中断将导致慢性疼痛。我们最近的研究表明，由omega-3不饱和脂肪酸DHA和EPA衍生的促拆分脂质介质(PRLM)，如分解素和保护素，是有效的炎症性和神经病理性疼痛的抑制剂。从机制上讲，PRLMS不仅使突触可塑性正常化，而且还抑制了脊髓中的神经胶质细胞的激活。溶血素也是TRPA1或TRPV1的内源性抑制物(IC50=1-10 nM)。然而，PRLMS的信号机制仍然难以捉摸。B-arrestin-2(Barr2)是一种典型的参与GPCRs脱敏的支架蛋白。然而，Barr2在调节NMDA受体功能和炎性/神经病理性疼痛中的独特作用尚不清楚。该应用程序的总体目标是调查barr2如何止痛，以及PRLMS是否通过barr2解决疼痛。我们的中心假设是Barr2，由一些PRLMS激活，通过掩盖ERK的激活来抑制疼痛，并有助于消解炎症性和神经病理性疼痛。我们将通过以下具体目标来验证这一假说：目的1，确定barr2对于炎性和神经病理性疼痛的解决是必不可少的，以及目标2，通过调节DRG神经元中的TRPA1/V1功能，脊髓神经元中的NMDAR功能，以及神经元和神经胶质细胞中ERK的激活，确定PRLMS和barr2在疼痛解决中的外周和中枢作用。我们认为，通过测试由PRLMS或/和Barr2介导的一种新的疼痛缓解途径，这一建议具有非常重要的意义。我们的方法是多学科的，结合了遗传操作(转基因小鼠、条件基因敲除小鼠、基因治疗)、电生理学和诱发疼痛和自发性疼痛(CPP)的行为测试。我们还将测试PRLMS在人类DRG神经元中的作用，以增加翻译潜力。这项拟议的研究不仅将确定一条有利于“止痛”的解决途径，还可能导致新的疼痛疗法的发展。

DESCRIPTION (provided by applicant): More than 30 million Americans suffer from unrelieved chronic pain, which is regarded as a disease with its own pathology. Current studies focus on how pain is induced, but it is unclear how acute pain naturally resolves. We hypothesize that disruption of local active pro-resolving processing will result in chronic pain. Our recent studies have shown that the pro-resolution lipid mediators (PRLMs) such as resolvins and protectins, derived from omega-3 unsaturated fatty acids DHA and EPA, are potent inhibitors of inflammatory and neuropathic pain. Mechanistically, PRLMs not only normalize synaptic plasticity but also suppress glial activation in the spinal cord. Resolvins are also potent endogenous inhibitors of TRPA1 or TRPV1 (IC50=1-10 nM). However, the signaling mechanisms of PRLMs are elusive. b-arrestin-2 (barr2) is a scaffold protein that is classically involved in desensitization of GPCRs. However, the unique role of barr2 in regulating NMDA receptor function and inflammatory/neuropathic pain is unknown. The overall goal of this application is to investigate how barr2 arrests pain and whether PRLMs resolve pain via barr2. Our central hypothesis is barr2, activated by some PRLMs, arrests pain and contributes to the resolution of inflammatory and neuropathic pain via masking ERK activation. We will test this hypothesis via the following specific aims: Aim 1, to establish that barr2 is essential for the resolution of inflammatory and neuropathic pain, and Aim 2, to define the peripheral and central roles of PRLMs and barr2 in pain resolution, by modulating TRPA1/V1 function in DRG neurons, NMDAR function in spinal cord neurons, and ERK activation in neurons and glia. We believe this proposal is highly significant by testing a novel pain resolution pathway mediated by PRLMs or/and barr2. Our approach is multidisciplinary that combines genetic manipulation (transgenic mice, conditional knockout mice, gene therapy), electrophysiology, and behavioral testing for evoked pain and spontaneous pain (CPP). We will also test the role of PRLMs in human DRG neurons to increase the translational potential. The proposed study will not only identify a pro- resolution pathway for "pain arrest" but may also lead to the development of novel pain therapeutics.