Role of glial derived prostaglandins in pain due to surgery

描述（由申请人提供）：在美国和世界范围内，手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，导致恢复延迟，临床健康结果受损，在某些情况下，持续疼痛的发展可能对生活质量产生长期影响。这部分是由于对术后疼痛的脊柱和外周机制的理解不完全。脊髓内的神经免疫相互作用越来越被认为是与几种持续疼痛状态相关的中枢致敏和触觉超敏的贡献者。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激酶信号的激活，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。许多主要传入源性因子已被确定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)，但它们在术后机械过敏和脊柱前列腺素产生调节中的作用尚未被研究。此外，尚不清楚在急性术后环境中，机械超敏反应、小胶质细胞激活和前列腺素生成的维持是否需要原发性传入活动。目前的建议将验证手术切口通过激活小胶质细胞、参与p38信号和增强前列腺素的产生来诱导脊髓神经元增敏和机械超敏的假设。特异性目的1将确定使用选择性抑制剂的大鼠手术切口后小胶质细胞激活是否有助于机械超敏反应和前列腺素的产生。特异性目标2将通过脊髓疗法中和CXC3L1和/或CCL2，确定导致这些现象的主要传入源因素；特异性目标3将通过选择性阻断TRPV1+主要传入纤维的方法，确定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：本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。这些研究的最终目的是为了更好地了解导致手术切口后机械超敏反应的脊柱机制，以确定新的和更有效的方法来控制术后疼痛

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