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 defining peripheral mechanisms of incisional pain. Our working hypothesis is that TRPV1 containing nociceptors that have ongoing activity as a consequence of incision signal nonevoked, guarding pain behavior and that this ongoing activity is due to NGF-induced sensitization of TRPV1 to heat and acid pH. In vivo primary afferent and dorsal horn cell recordings, in vitro primary afferent recordings, transgenic mice, immunohistochemistry, and behavioral studies will be used in concert to examine the mechanisms that contribute to activation and sensitization of nociceptors by incision. Our working hypothesis is that 1) guarding pain behaviors and spontaneous acitivity in nociceptors and dorsal horn neurons will be exacerbated and reduced by warming and cooling the hindpaw, respectively. 2) Capsaicin treatment will cause loss of CGRP and IB4 (C-fibers) staining but not N52 (A-fibers) staining. Capsaicin treatment will reduce heat hyperalgesia and guarding behaviors but not mechanical hyperalgesia. Certain doses may differentiate guarding and heat hyperalgesia. 3) Heat, pH and NGF responses but not mechanical responses will be decreased by capsaicin in the incised glabrous skin nerve preparation. 4) C-fibers from incised congenic TRPV1 KO mice will have decreased response to heat, pH and NGF compared to incised C57BI6 mice. Few spontaneously active afferents and dorsal horn neurons will be present in vivo from incised rats after destruction of TRPV1 containing fibers. 5) NGF will be increased in incised skin but TRPV1 and Trk A receptors will be unchanged after incision indicating NGF is contributing to pain by producing acute sensitization of nociceptors. The results of these studies will provide important new insights into the mechanisms that subserve nociceptor activation, nonevoked, guarding pain behavior and heat hyperalgesia as a consequence of incisional injury. A separate pathway, likely an A-fiber mediated pathway, is sufficient to transmit the enhanced mechanical responses. ? ? ?
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