Non-steroidal anti-inflammatory drugs (NSAIDs) are widely employed for pain after tissue injury. Their common is inhibition of cyclooxygenase (COX), an enzyme converting arachidonic acid (AA) generated by phospholipases (PLA2) to prostaglandins (PG). While early work hypothesized peripheral mechanisms, we showed a spinal antihyperalgesic action of NSAIDs and more recently of PLA2 inhibitors. The thesis of our work is that peripheral inflammation and injury initiates a spinal cascade that underlies hyperalgesia. An element of this cascade involves activation by afferent transmitters of one or more constitutive spinal PLA2 isozymes that provide AA for catalysis to PGs by two constitutive spinal COX isozymes. PGs sensitize spinal terminals and contribute to facilitated nociceptive processing. In addition to acute effects, afferent input along with circulating pro-inflammatory agents (TNFa, ILIB or LPS: lipopolysacharide) activate regulatory factors (e.g. NFKB and P38 MAP kinases) that upregulate spinal PLA2 and COX-2 isozyme expression in neuronal and non-neuronal cells (astrocytes/microglia). These interactions lead to enhanced spinal release of PGs and an increased spinal excitability. This proposal presents long-term studies which seek to i) define the pharmacology of spinal PLA2 and COX-2 isozymes contributing to the hyperalgesic state; ii) identify spinal isozyme distribution in neuronal/non-neuronal cells and iii) characterize neural and circulating factors that induce spinal expression of these isozymes. In this work, the hyperalgesic state and the correlated release of spinal PGE2/glutamate using in vivo spinal dialysis will be examined with respect to the effects of spinally-delivered COX-l and 2 inhibitors, PLA2 inhibitors and intrathecal COX-1 and 2 antisenses. The effects of spinal activation and IV cytokines (IL1BrFNFcilLPS) on expression of spinal COX-l and 2 protein (Western blots / immunohistochemistry) and PLA2 mRNA (PCRfNorthern blots) will be examined. The clinical relevance of these studies is emphasized given that non-specific COX and COX-2 inhibitors are potent in managing pain states ranging from postoperative to cancer pain. Their efficacy demonstrates the importance of the role played by the PLA2-COX cascade. That neurons/astrocytes constitutively express PLA2/COX and that tissue injury and cancer leads to activated spinal neurons and astrocytes and the upregulation of spinal PLA2/COX expression indicates important mechanisms that subserve the efficacy that NSAIDs have in managing perioperative and cancer pain.
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