Sex differences in the cellular mechanisms of chronic pain
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AbstractChronic pain is a debilitating condition that negatively impacts the quality of life of those afflicted. Despite significant advancements in the development of anaesthetics and analgesics that inhibit nociception, including opioids and non-opioids, these drugs are largely ineffective in the treatment of chronic pain. Sex differences in pain mechanisms can contribute to the variability of response to treatment in patients, however much remains unknown of the cellular and molecular mechanisms that underlie such differences. This thesis investigates sex differences in the mechanisms underlying two experimental models of chronic pain: neuropathic and post surgical pain. My overarching hypothesis is that spinal microglia and astrocytes differentially modulate the development and expression of chronic pain in male and female rodents. In this thesis, I report that activation of Pannexin 1 (Panx1) channels expressed on spinal microglia are critically involved in the development and expression of mechanical allodynia in males but not females following peripheral nerve injury. Depletion of microglial Panx1 channels prevented the development, and reversed the expression, of mechanical allodynia following nerve injury in males but not females. Furthermore, I provide direct evidence that Panx1 activation induced the release of pro-inflammatory cytokine vascular endothelial growth factor (VEGF) specifically from male-derived microglia, which critically modulates the expression of mechanical allodynia. I then explore sex differences in the cellular mechanisms of chronic pain using the Skin-muscle incision-retraction (SMIR) experimental rodent model of post surgical pain. I demonstrated that females have an attenuated recovery from SMIR surgery compared to males, and that prolonged astrocyte activation may play a critical role in modulating this delay. Additionally, I demonstrate that following SMIR surgery, females maintain elevated spinal levels of monocyte chemoattractant protein 1 (MCP1), a pro-inflammatory cytokine released primarily by astrocytes in the central nervous system, that contribute to the attenuated recovery of post surgical pain in females. Future studies are necessary to dissect the cellular machinery modulating the release MCP1 and the implications for post-operative pain. In conclusion, the findings from this thesis reveal that spinal microglia and astrocytes differentially modulate the expression of neuropathic and post surgical pain in males and females.
CitationFan, C. Y. (2020). Sex differences in the cellular mechanisms of chronic pain (Unpublished doctoral thesis). University of Calgary, Calgary, AB.
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