Role of glial derived prostaglandins in pain due to surgery

描述（由申请人提供）：在美国和全球范围内，术后疼痛的管理对于接受外科手术的个体来说是一项持续的临床挑战。许多患者没有接受足够的镇痛支持，导致延迟恢复，损害临床健康结果，在某些情况下，发生持续性疼痛，可能对生活质量产生长期影响。这部分是由于不完全理解脊柱和外周机制负责术后疼痛。脊髓内的神经免疫相互作用越来越被认为是与几种持续性疼痛状态相关的中枢致敏和触觉超敏反应的贡献者。然而，神经免疫相互作用在术后疼痛状态的性质和功能意义还没有得到很好的理解。小胶质细胞活化的标志是细胞骨架重排、细胞表面受体的上调、p38 p MAP激酶信号传导的活化以及增加的脊髓合成和释放的胡萝卜素和各种促炎细胞因子。已经确定了一些初级传入衍生因子，包括趋化因子CCL 2和fractalkine（CX 3CL 1），有助于组织损伤后的小胶质细胞活化，但它们在术后机械超敏反应和脊髓前列腺素产生的调节中的作用尚未得到研究。此外，目前还不清楚初级传入活动是否需要维持机械超敏反应，小胶质细胞活化，前列腺素的生产在急性术后设置。目前的建议将测试的假设，手术切口诱导脊髓神经元和机械超敏性的部分通过激活小胶质细胞，从事p38信号和增强前列腺素的生产增加的敏感性。具体目标1将使用选择性抑制剂确定小胶质细胞活化是否有助于大鼠手术切口后的机械超敏反应和前列腺素产生。具体目标2将使用中和CXC 3L 1和/或CCL 2的脊柱治疗来确定导致这些现象的初级传入衍生因素，具体目标3将使用选择性阻断TRPV 1+初级传入纤维的方法来确定来自切口部位的初级传入输入与这些现象的相关性。公共卫生相关性：该提案将采用各种与疼痛研究相关的体内药理学、外科学、行为学和生物化学技术。这些研究的最终目的是更好地了解导致手术切口后机械性超敏反应的脊柱机制，以确定新的和更有效的方法来管理术后疼痛

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