Role of glial derived prostaglandins in pain due to surgery

描述(由申请人提供)：术后疼痛的管理在美国和世界各地对接受外科手术的个人来说是一个持续的临床挑战。许多患者没有得到足够的止痛支持，导致延迟康复，损害临床健康结果，在某些情况下发展成可能对生活质量产生长期影响的持续性疼痛。这在一定程度上是由于对导致术后疼痛的脊柱和外周机制的了解不完全。脊髓内的神经免疫相互作用越来越被认为是中枢敏感化和与几种持续性疼痛状态相关的触觉超敏的贡献者。然而，术后疼痛状态下神经免疫相互作用的性质和功能意义还不是很清楚。小胶质细胞活化的特征是细胞骨架重排，细胞表面受体上调，激活p38p MAPK信号，增加脊髓合成和释放前列腺素和各种促炎细胞因子。许多主要的传入衍生因子参与了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调节脊髓前列腺素产生中的作用尚未被研究。此外，尚不清楚急性术后环境中是否需要初级传入活动来维持机械超敏反应、小胶质细胞激活和前列腺素的产生。目前的提议将检验这一假说，即手术切口通过激活小胶质细胞、参与p38信号转导和促进前列腺素产生来部分地诱导脊髓神经元的敏感化和机械过敏。具体目标1将确定使用选择性抑制剂的大鼠手术切开后，小胶质细胞的激活是否有助于机械过敏和前列腺素的产生。特定目标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初级传入衍生因素，而特定目标3将使用选择性阻断TRPV1+初级传入纤维的方法来确定从切开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：这项提案将采用与疼痛研究相关的各种体内药理学、外科手术、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开后机械过敏的脊柱机制，以便找出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