TrkA and PKC-epsilon in thermal burn-induced mechanical hyperalgesia in the rat.
Although mechanical hyperalgesia associated with medical procedures is the major source of severe pain in burn-injured patients, little is known about its underlying mechanism. One reason for this has been the lack of a model for mechanical hyperalgesia at the site of injury. We have modified an established partial-thickness burn model in the rat to produce long-lasting primary mechanical hyperalgesia, which is present from the first measurement at 0.5 h, reaches a maximum at 3 days, and is still significant after 7 days. Because nerve growth factor (NGF), which is elevated in burn-injured tissue, produces mechanical hyperalgesia and activates protein kinase C (PKC)-epsilon, a key mediator in inflammatory and neuropathic pain, we used this model to evaluate the role of the NGF receptor, tyrosine-receptor kinase A (TrkA), and PKC-epsilon in burn-induced primary mechanical hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides to TrkA and PKC-epsilon, starting 3 days before inducing a burn injury, caused dose-related decrease of burn-induced primary mechanical hyperalgesia. In addition, intradermal injection of a PKC-epsilon-selective inhibitor eliminated hyperalgesia. Our model provides a method to elucidate the underlying mechanism of burn-injury pain as well as to screen for targets for novel analgesic treatments of this important clinical condition.


CONCLUSIONS
This manuscript presents the first model of thermal injury-induced mechanical hyperalgesia which mimics prolonged duration of clinical burn injury pain. We also perform proof of concept experiments demonstrating that our model provides a method to elucidate the mechanism of this important clinical condition.
Summer
Gretchen J
GJ
Department of Physiological Nursing, School of Nursing, University of California, San Francisco, USA. gretchen.summer@ucsf.edu
Puntillo
Kathleen A
KA
Miaskowski
Christine
C
Dina
Olayinka A
OA
Green
Paul G
PG
Levine
Jon D
JD
D000818:Animals; D002056:Burns / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000008:administration & dosage; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000502:physiology; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D004791:Enzyme Inhibitors; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; C061479:protein kinase inhibitor peptide; D020917:Receptor, trkA; D051744:Protein Kinase C-epsilon