Mechanisms of pain following thermal injury

Thermal injury induces a profound inflammatory response, which is manifested locally and systemically. Pain is an integral part of this response. However, little is known about the mechanisms of burn injury pain. Clinically, pain behaviors suggest that both acute and chronic pain mechanisms are induced following thermal injury. However, mechanisms of pain following thermal injury have not received the attention it deserves. To be sure, the models and laboratory assays necessary to tease apart the complex mechanisms that contribute to burn pain have not been well developed. However, understanding the molecular events that occur in cells subjected to noxious heat is critical to the advance the development of therapeutic targets for analgesic therapies following thermal injury. This dissertation establishes a program of research to investigate the mechanisms of pain following thermal injury. Section I provides a review of the problem of burn pain, the underlying mechanisms associated with burn injury that may contribute to burn pain, the types of pain associated with burn injury, and pain management strategies across the continuum of burn care. Section II describes an animal model that was developed and tested to investigate the mechanisms of primary mechanical hyperalgesia induced by a thermal burn. The model demonstrates for the first time the profound intensity and long duration of burn-induced hyperalgesia over the course of one week. The model is important because it allows for the continuous observation in real time of behavioral changes in nociceptive threshold that occurred before, during, and after exposure to a thermal burn. Section III describes a series of experiments that were conducted using this model to investigate the contribution of two mediators of inflammatory pain: nerve growth factor (NGF) and protein kinase C-epsilon (PKCepsilon). Findings from these experiments suggest that NGF and PKCepsilon play important roles in the mechanisms by which burns induce hyperalgesia. Future research will investigate these and other mediators of acute pain following burn injury as well as those that may lead to chronic pain states. The investigation of mechanisms of pain following thermal burns is a priority program of research that has significant clinical relevance.