Resolution pathway of pain

描述（申请人提供）：超过3000万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。目前的研究集中在疼痛是如何诱发的，但尚不清楚急性疼痛是如何自然消退的。我们推测，局部主动促消退过程的中断将导致慢性疼痛。我们最近的研究表明，促消退脂质介质（PRLM），如resolvins和protectins，来源于ω-3不饱和脂肪酸DHA和EPA，是炎症和神经性疼痛的有效抑制剂。从机制上讲，PRLM不仅使突触可塑性正常化，而且还抑制脊髓中的胶质细胞活化。Resolvins也是TRPA 1或TRPV 1的有效内源性抑制剂（IC 50 =1-10 nM）。然而，PRLM的信号传导机制是难以捉摸的。b-抑制蛋白-2（barr 2）是一种支架蛋白，其典型地参与GPCR的脱敏。然而，barr 2在调节NMDA受体功能和炎性/神经性疼痛中的独特作用尚不清楚。本申请的总体目标是研究barr 2如何抑制疼痛以及PRLM是否通过barr 2缓解疼痛。我们的中心假设是barr 2，由一些PRLM激活，通过掩蔽ERK激活抑制疼痛并有助于炎症和神经性疼痛的解决。我们将通过以下具体目标来测试这一假设：目标1，确定barr 2对于炎症性和神经性疼痛的消退是必不可少的，目标2，通过调节DRG神经元中的TRPA 1/V1功能、脊髓神经元中的NMDAR功能以及神经元和神经胶质中的ERK激活来定义PRLM和barr 2在疼痛消退中的外周和中枢作用。我们相信这一建议是非常重要的，通过测试一种新的疼痛解决途径介导的PRLM或/和barr 2。我们的方法是多学科的，结合了遗传操作（转基因小鼠，条件性基因敲除小鼠，基因治疗），电生理学和行为测试诱发疼痛和自发性疼痛（CPP）。我们还将测试PRLM在人类DRG神经元中的作用，以增加翻译潜力。这项拟议中的研究不仅将确定一个“疼痛停止”的前解决途径，而且还可能导致新的疼痛治疗方法的发展。

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.