Postoperative, incisional pain is a unique but common form of acute pain. Since effective postoperative analgesia reduces morbidity following surgery, new treatments continue to be investigated. The proposal is dedicated toward studies of the mechanisms that subserve acute postoperative pain, It is through the study of mechanisms that a better understanding of incisional pain can be achieved and new treatments can be advanced. The work proposed will specifically characterize the mechanisms for incisional pain at the neuronal level in the dorsal horn. Neurochemical and neurophysiological approaches will be used in concert to examine the mechanisms that contribute to the development and maintenance of primary and secondary hyperalgesia after incision. Our working hypothesis is that glutamate and aspartate act on nonNMDA (N-methyl-D-aspartate) receptors to induce changes in spinal cord processing and to maintain the sensitization of dorsal horn neurons. Specifically, we will: (1) Investigate the effect of NMDA, nonNMDA and metabotropic excitatory amino acid receptor antagonists on the response properties of spinal cord dorsal horn neurons sensitized by an incision. (2) Determine the role of NMDA and nonNMDA receptors, including calcium-permeable AMPA (amino-3-hydroxy-5-methylisoxazole-4-propionic acid ) receptors and kainate receptors, on the secondary hyperalgesia caused by an incision of the gastrocnemius region. Neurophysiologic studies will determine the effect of NMDA and nonNMDA receptor antagonists on a specific measure of central sensitization of dorsal horn neurons caused by incision and in so doing reveal the specific contribution of central sensitization to pain behaviors. (3) Confirm that incision results in an increased basal or evoked release of the excitatory amino acids, aspartate and glutamate, in the spinal cord dorsal horn. These studies will use microdialysis to examine the time course and magnitude of glutamate and aspartate release during and after incision under quiescent conditions and conditions of repetitive stimulation. Insights gained into the role of excitatory amino acids, and in particular the role of calcium-permeable AMPA and kainate receptors, will advance our understanding of postoperative incisional pain and provide a basis for rationale design of new pharmacologic treatment
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