Role of glial derived prostaglandins in pain due to surgery

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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