Peripheral nerve function is compromised when there is a sustained mechanical stimulus to the nerve as it passes through a potentially constrained space. Based on the location and magnitude of this mechanical stimulus, a chronic nerve injury (CNI) will manifest with different signs and symptoms. Some of the more commonly afflicted areas include the carpal tunnel, cubital tunnel, and spinal nerve root canal. These pathologic conditions affect millions of individuals as they are limited by the pain and loss of function associated with their condition. After the patient has failed conservative treatment, surgical intervention involving a mechanical decompression of the constrained space is performed. Yet, surgical decompression is often ineffective in restoring function and eliminating pain. The surgical treatment reduces some of the symptoms and should halt the progression of the pathologic process. But based on the length of time and severity of the sustained mechanical stimulus, the histopathologic changes of the peripheral nerve may not be reversed with surgical management. All cell types within the peripheral nerve are eventually affected by CNI. As the change in axonal number and function is one of the last events in CNI, this process contrasts to Wallerian degeneration where the loss of axonal integrity leads to the cascade of events. With CNI, Schwann cells decrease in number, fibroblasts proliferate and increase type I collagen expression, and eventually axonal number and function diminish. The focus of this project is to better characterize how a sustained mechanical stimulus to a peripheral nerve is transduced into a pathophysiologic response in an animal model. The central hypothesis of this project is that CNI-initiates a cascade of events that leads to Schwann cell death, and that the loss of Schwann cells creates an inhospitable environment for axons in the nerve. We plan : 1) To determine if the histopathologic changes associated with a CNI are geographically related to the site of injury by performing quantitative morphometric analyses of the peripheral nerve to determine the pattern and timing of Schwann cell loss, fibroblast proliferation, and axonal loss; 2) To determine if the decrease in Schwann cell number that occurs with a chronic nerve injury is the result of Schwann cell apoptosis; and 3) To determine if the ischemic component of a chronic nerve injury induces an up-regulation of nitric oxide synthase (NOS) mRNA and the expression of the NOS enzyme in Schwann cells at different stages of the chronic nerve injury. Successful completion of these studies will provide a greater understanding of the pathogenesis of CNI so that more effective treatment modalities may be developed.