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.PerspectiveThis 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.