Resolution pathway of pain

描述（由申请人提供）：超过3000万美国人患有无法缓解的慢性疼痛，这被视为一种具有自身病理学的疾病。目前的研究集中在疼痛是如何引起的，但急性疼痛是如何自然消退的还不清楚。我们假设局部主动解决过程的中断将导致慢性疼痛。我们最近的研究表明，从omega-3不饱和脂肪酸DHA和EPA中提取的溶解蛋白和保护蛋白等促溶解脂质介质（PRLMs）是炎症和神经性疼痛的有效抑制剂。在机制上，PRLMs不仅使突触可塑性正常化，而且还抑制脊髓中的胶质细胞激活。溶解蛋白也是TRPA1或TRPV1的有效内源性抑制剂（IC50=1-10 nM）。然而，PRLMs的信号机制尚不明确。b-阻滞蛋白2 （barr2）是一种支架蛋白，通常参与gpcr的脱敏。然而，barr2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。本应用程序的总体目标是研究barr2如何抑制疼痛以及prlm是否通过barr2解决疼痛。我们的中心假设是barr2被一些PRLMs激活，通过掩盖ERK激活来抑制疼痛并有助于解决炎症性和神经性疼痛。我们将通过以下具体目标来验证这一假设：目标1，确定barr2对炎症性和神经性疼痛的解决至关重要；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功能以及神经元和胶质细胞中的ERK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bar2介导的新型疼痛解决途径，这一提议具有重要意义。我们的方法是多学科的，结合了基因操作（转基因小鼠、条件敲除小鼠、基因治疗）、电生理学和诱发性疼痛和自发性疼痛（CPP）的行为测试。我们还将测试PRLMs在人类DRG神经元中增加翻译电位的作用。提出的研究不仅将确定“疼痛停止”的前解决途径，而且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.