Mechanistic Exploration of Exercise and Neuropathic Pain
Date
2023-12-08
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Abstract
Peripheral nerve injury caused by disease or damage of the peripheral nerves is often accompanied by neuropathic pain, a debilitating chronic pain condition plagued by abnormal pain sensitivity. Current treatment options are limited and provide sub-optimal pain relief. Recent pre- clinical and clinical studies suggest that exercise reduces pain and improves motor recovery following nerve injury, but how this occurs is not clear. In this study, I characterized the development of neuropathic pain using the spared nerve injury (SNI) model which produces robust mechanical allodynia, a painful response to an innocuous stimulus. Utilizing a voluntary running wheel exercise paradigm, I identified key timepoints after nerve injury where exercise improves recovery following the development of mechanical allodynia. Focusing on the spinal cord as it is a hub for sensory nerve input and contains important motor circuitry that is altered following nerve injury, I assessed the impact of SNI and exercise on sensory peripheral nerve endings and spinal motor neurons as nerve injury induces persistent motor deficits. I also test the hypothesis that exercise modulates microglia, immune cells residing in the central nervous system that become reactive following SNI, contributing to the sequelae of neuropathic pain. Using a genetic mouse strain to visually distinguish peripheral immune cells from resident microglia, I demonstrate that SNI increases, while exercise decreases, the infiltration of peripheral immune cells into the spinal cord at a key timepoint where nerve injured animals given access to a running wheel no longer display mechanical allodynia. Further analysis of the spinal cord using gene profiling arrays uncover dysregulated gene expression due to SNI and exercise unique to the different regions of the spinal cord related to sensory and motor processing. Specifically, I identify genes Grin2b, Ptges3, and Faah that are over expressed two weeks after SNI in animals given access to a running wheel. At four weeks after SNI, expression of these genes is comparable to sham control. Ultimately these findings uncover specific dorsal and ventral horn temporal disease related transcriptional changes engaged by exercise that future studies may target to improve the treatment of neuropathic pain by mimicking the beneficial effects of exercise.
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Vogel, H. (2023). Mechanistic exploration of exercise and neuropathic pain (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.