Many people suffer from chronic neuropathic pain (e.g., causalgia, trigeminal neuralgia) with little hope for relief. This pessimism persists because there is little understanding of the changes occurring in the nervous system during the development and progression of neuropathic pain. An experimental model of nerve injury in the rat, which results in the development of neuropathic pain, was introduced in 1988. This model, referred to as the chronic constriction model of nerve injury (CCI), appears to be the first that allows evaluation of changes in the nervous system and the possibility of correlating these changes to the behavioral appearance of hyperalgesia, allodynia and spontaneous pain (dysesthesia). The CCI provides the very real possibility that changes in the nervous system underlying the development of chronic neuropathic pain finally may be amendable to elucidation. The goals of this research are to use the CCI to evaluate changes taking place in the nervous system during the early stages of the injury. In the first project, electrophysiological recordings from primary afferent fibers and from neurons at the origin of the spinothalamic tract will help evaluate alterations in the response properties of sensory neurons during the development of neuropathic pain. The second project will evaluate differences between the CCI injury, with its accompanying neuropathic pain, and a complete transection of the sciatic nerve. This project will use an antibody to Fos-protein (the nuclear phosphoprotein product of the mammalian proto-oncogene c-fos) to label neurons in the spinal cord that express Fos after an injury to the sciatic nerve. The goal is to understand more about the spinal location of neurons ex- pressing Fos and to evaluate differences in expression between the two nerve injuries. The third project Consists of two studies. Evaluation of increases in the spinal levels of the endogenous opioid peptide dynorphin correlated with development of behavioral hyperalgesia after the CCI will compose the first study. The second study will evaluate the importance of two different factors associated with primary afferent fibers on the increase in spinal levels of dynorphin. The goal of this study is to evaluate the importance of glutamate released from injured primary afferent fibers and the importance of injured C fibers on the increase in dynorphin seen after the CCI. Elucidating the changes occurring in the nervous system during development of neuropathic pain provide hope for finding interventions. Once the changes are understood, it will be possible to begin clinical trials testing interventions capable of reversing these changes and preventing the development of neuropathic pain. Additionally, understanding the underlying changes provide opportunity for producing new treatments that may significantly improve the prognosis of patients already suffering from neuropathic pain.
