Role of glial derived prostaglandins in pain due to surgery

神经胶质衍生的前列腺素在手术引起的疼痛中的作用

• 批准号: 7883579
• 负责人: Christopher Michael Peters
• 金额: $ 5.05万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883579
• 关键词: Acute; Analgesics; Behavioral; Biochemical; CCL2 gene; CX3CL1 gene; Cell Surface Receptors; Clinical; DNA Sequence Rearrangement; Development; Fiber; Fractalkine; Goals; Health; Hypersensitivity; Individual; Injury; MAPK14 gene; Maintenance; Mechanics; Microglia; Mitogen-Activated Protein Kinases; Nature; Neurons; Operative Surgical Procedures; Outcome; Pain; Pain Research; Patients; Peripheral; Persistent pain; Postoperative Pain; Postoperative Period; Production; Prostaglandin Production; Prostaglandins; Quality of life; Rattus; Receptor Activation; Recovery; Regulation; Role; Signal Transduction; Site; Spinal; Spinal Cord; Surgical incisions; TRPV1 gene; Tactile; Techniques; Testing; Tissues; United States; Up-Regulation; central sensitization; chemokine; cytokine; in vivo; inhibitor/antagonist; novel; public health relevance

DESCRIPTION (provided by applicant): The management of postoperative pain is a continuing clinical challenge in the United States and worldwide for individuals undergoing surgical procedures. Many patients do not receive adequate analgesic support leading to delayed recovery, compromised clinical health outcomes and in some instances the development of persistent pain that can have a long term impact on quality of life. This is in part due to an incomplete understanding of the spinal and peripheral mechanisms responsible for postoperative pain. Neuroimmune interactions within the spinal cord are increasingly recognized as contributors to central sensitization and tactile hypersensitivity associated with several persistent pain states. However, the nature and functional significance of neuroimmune interactions in postoperative pain states is not well understood. The hallmarks of microglial activation are cytoskeletal rearrangement, upregulation of cell surface receptors, activation of p38p MAP kinase signaling, and increased spinal synthesis and release of prostaglandins and various proinflammatory cytokines. A number of primary afferent derived factors have been identified that contribute to microglial activation following tissue injury including the chemokines CCL2 and fractalkine (CX3CL1), however their role in postsurgical mechanical hypersensitivity and the regulation of spinal prostaglandin production have not been examined. Furthermore, it is unclear if primary afferent activity is required for the maintenance of mechanical hypersensitivity, microglial activation, and prostaglandin production in the acute postoperative setting. The current proposal will test the hypothesis that surgical incision induces increased sensitization of spinal neurons and mechanical hypersensitivity in part by activating microglia, engaging p38 signaling and enhancing prostglandin production. Specific Aim 1 will determine if microglial activation contributes to mechanical hypersensitivity and prostaglandin production following surgical incision in rats using selective inhibitors. Specific Aim 2 will determine the primary afferent derived factors that contribute to these phenomena using spinal therapies that neutralize CXC3L1 and/or CCL2 and Specific Aim 3 will determine the relevance of primary afferent input from the incision site to these phenomena using an approach to selectively block TRPV1+ primary afferent fibers. PUBLIC HEALTH RELEVANCE: This proposal will employ a variety of in vivo pharmacological, surgical, behavioral and biochemical techniques relevant to pain research. The ultimate goal of these studies is to gain a better understanding of spinal mechanisms that contribute to mechanical hypersensitivity following surgical incision in order to identify novel and more effective approaches to manage postoperative pain

描述（由申请人提供）：对于美国和全世界接受外科手术的个人来说，术后疼痛的管理是一个持续的临床挑战。许多患者没有得到足够的镇痛支持，导致康复延迟、临床健康结果受损，在某些情况下还会出现持续性疼痛，对生活质量产生长期影响。这部分是由于对导致术后疼痛的脊柱和外周机制的不完全了解。人们越来越认识到脊髓内的神经免疫相互作用是导致与几种持续性疼痛状态相关的中枢敏化和触觉超敏反应的因素。然而，术后疼痛状态中神经免疫相互作用的性质和功能意义尚不清楚。小胶质细胞激活的标志是细胞骨架重排、细胞表面受体上调、p38p MAP 激酶信号传导激活以及前列腺素和各种促炎细胞因子的脊柱合成和释放增加。已确定许多主要传入源因子有助于组织损伤后小胶质细胞的激活，包括趋化因子 CCL2 和 fractalkine (CX3CL1)，但它们在术后机械超敏反应和脊髓前列腺素产生调节中的作用尚未得到研究。此外，尚不清楚在急性术后环境中维持机械过敏、小胶质细胞激活和前列腺素产生是否需要初级传入活动。目前的提案将检验这样的假设：手术切口部分通过激活小胶质细胞、参与 p38 信号传导和增强前列腺素的产生来诱导脊髓神经元的敏感性增加和机械过敏。具体目标 1 将确定使用选择性抑制剂对大鼠进行手术切口后，小胶质细胞激活是否会导致机械过敏和前列腺素产生。具体目标 2 将使用中和 CXC3L1 和/或 CCL2 的脊柱疗法来确定导致这些现象的主要传入衍生因素，具体目标 3 将使用选择性阻断 TRPV1+ 主要传入纤维的方法确定来自切口部位的主要传入输入与这些现象的相关性。公共卫生相关性：该提案将采用与疼痛研究相关的各种体内药理学、外科、行为和生化技术。这些研究的最终目标是更好地了解导致手术切口后机械过敏的脊柱机制，以便找到新的、更有效的方法来控制术后疼痛