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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM055831-11
Application #
7254228
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
1997-05-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
11
Fiscal Year
2007
Total Cost
$307,928
Indirect Cost
Name
University of Iowa
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Xu, Jun; Brennan, Timothy J (2011) The pathophysiology of acute pain: animal models. Curr Opin Anaesthesiol 24:508-14
Brennan, Timothy J (2011) Pathophysiology of postoperative pain. Pain 152:S33-40
Kang, Sinyoung; Wu, Chaoran; Banik, Ratan K et al. (2010) Effect of capsaicin treatment on nociceptors in rat glabrous skin one day after plantar incision. Pain 148:128-40
Xu, Jun; Brennan, Timothy J (2010) Guarding pain and spontaneous activity of nociceptors after skin versus skin plus deep tissue incision. Anesthesiology 112:153-64
Wu, Chaoran; Erickson, Mark A; Xu, Jun et al. (2009) Expression profile of nerve growth factor after muscle incision in the rat. Anesthesiology 110:140-9
Kang, Sinyoung; Brennan, Timothy J (2009) Chemosensitivity and mechanosensitivity of nociceptors from incised rat hindpaw skin. Anesthesiology 111:155-64
Spofford, Christina M; Ashmawi, Hazem; Subieta, Alberto et al. (2009) Ketoprofen produces modality-specific inhibition of pain behaviors in rats after plantar incision. Anesth Analg 109:1992-9
Xu, Jun; Brennan, Timothy J (2009) Comparison of skin incision vs. skin plus deep tissue incision on ongoing pain and spontaneous activity in dorsal horn neurons. Pain 144:329-39
Xu, Jun; Richebe, Philippe; Brennan, Timothy J (2009) Separate groups of dorsal horn neurons transmit spontaneous activity and mechanosensitivity one day after plantar incision. Eur J Pain 13:820-8
Banik, Ratan K; Brennan, Timothy J (2009) Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain 141:41-51

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