Resolution pathway of pain

疼痛的缓解途径

• 批准号: 8815927
• 负责人: RU-RONG JI
• 金额: $ 34.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8815927
• 关键词: Absence of pain sensation; Acute Pain; American; CD59 Antigen; Capsaicin; Cells; Cytokine Activation; Development; Disease; Electrophysiology (science); Exhibits; Formalin; Goals; Human; Impairment; Inflammation; Inhibitory Concentration 50; Injection of therapeutic agent; Knockout Mice; Lead; Lentivirus Vector; Masks; Measures; Mediating; Microinjections; Mitogen-Activated Protein Kinases; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurons; Nociception; Nociceptors; Omega-3 Fatty Acids; Opioid Receptor; Paclitaxel; Pain; Pathology; Pathway interactions; Peripheral; Phosphorylation; Process; Resolution; Role; Scaffolding Protein; Signal Transduction; Small Interfering RNA; Spinal; Spinal Cord; Spinal Ganglia; Synaptic Transmission; Synaptic plasticity; TRPV1 gene; Testing; Therapeutic; Transgenic Mice; Unsaturated Fatty Acids; arrestin 2; behavior test; chemokine; chemotherapy; chronic neuropathic pain; chronic pain; constriction; desensitization; gene therapy; genetic manipulation; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; interdisciplinary approach; lipid mediator; multidisciplinary; mustard oil; nerve injury; neuroprotectin D1; novel; painful neuropathy; patch clamp; preference; prevent; public health relevance; receptor function; spontaneous pain

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.

描述（由申请人提供）：超过3000万美国人患有不受欢迎的慢性疼痛，被认为是一种具有自己病理学的疾病。当前的研究集中于如何诱发疼痛，但目前尚不清楚急性疼痛如何自然能够解决。我们假设局部主动促进处理处理的破坏将导致慢性疼痛。我们最近的研究表明，源自Omega-3不饱和脂肪酸DHA和EPA的促脂质脂质介质（PRLM）是炎症和神经性疼痛的有效抑制剂。从机械上讲，PRLM不仅使突触可塑性正常，而且还抑制脊髓中的神经胶质激活。 resolvins也是TRPA1或TRPV1（IC50 = 1-10 nm）的有效内源性抑制剂。但是，PRLM的信号传导机制是难以捉摸的。 B-arrestin-2（BARR2）是一种脚手架蛋白，在GPCR的脱敏上经常涉及。但是，Barr2在调节NMDA受体功能和炎症/神经性疼痛中的独特作用尚不清楚。该应用的总体目标是研究BARR2如何阻止疼痛以及PRLMS是否通过BARR2解决疼痛。我们的中心假设是BARR2，由一些PRLM激活，阻止疼痛，并通过掩盖ERK激活来解决炎症和神经性疼痛。我们将通过以下特定目的来检验该假设：目的1，确定BARR2对于解决炎症和神经性疼痛是至关重要的，目的是定义PRLMS和BARR2在疼痛中的周围和中心作用，通过调节DRG神经元中的TRPA1/V1在NMDAR NEURONS中调节trpA1/v1在疼痛中的作用，NEREN NEURONS和ERK CORTIA，ERK和ERK CORTIA，ERK和ERK和ERK和ERK和ERK，以及ERK和ERK，以及ERK和ERK，以及ERK和ERK。我们认为，通过测试由PRLMS或/和BARR2介导的新型疼痛分辨率途径，这一建议非常重要。我们的方法是多学科的，结合了遗传操纵（转基因小鼠，有条件的基因敲除小鼠，基因治疗），电生理学和诱发疼痛和自发疼痛的行为测试（CPP）。我们还将测试PRLM在人DRG神经元中的作用，以提高翻译潜力。拟议的研究不仅将确定“疼痛抑制”的解决途径，而且还可能导致新型疼痛治疗的发展。