Molecular Determinants of Spinal Hyperexcitability in Rat and Human Models of Pathological Pain

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Dedek, Annemarie




Chronic pain is a health crisis with few safe and effective treatments. Understanding the mechanisms that drive chronic pain predicate the development of novel therapeutics for the disease. The superficial dorsal horn (SDH) is an integral part of the pain-processing circuit. Nociceptive output from the SDH is mediated by a homeostatic balance of inhibition and excitation, resulting in pain responses in healthy individuals that are proportional to noxious stimuli. In chronic pain, the balance between inhibition and excitation degrades, resulting in spinal hyperexcitability and an increase in pain outputs to the brain. To study the molecular processes that disrupt the balance of inhibition and excitation within SDH circuitry, we paired a male rat ex vivo pain model with in vivo models. We found that the loss of potassium-chloride cotransporter 2-dependent inhibition (disinhibition) and facilitated excitation (marked by potentiation of excitatory N-methyl-D-aspartate receptors, NMDARs) are linked. We determined that downregulation of the phosphatase STEP61 is the linker between disinhibition and NMDAR potentiation in male rats. To address the translational divide that exists between basic science rodent research and clinical trials, we developed an ex vivo pathological pain model using human organ donor tissue. Using this model, we found that the STEP61-mediated link between disinhibition and NMDAR potentiation is conserved in the SDH of male humans. Despite that chronic pain affects women more often than men, the molecular underpinnings of chronic pain have been studied almost exclusively in males. Surprisingly, we found that NMDARs are not potentiated in our female rodent pain models, and that protein markers of disinhibition and facilitated excitation remain unchanged. This demonstrates a sex difference in neuronal pain processing in rodents within the SDH. Further, we used human tissue models to discover that this sex difference is conserved between rats and humans. We conclude that loss of STEP61 links disinhibition and facilitated excitation in male rats and humans, but this mechanism of spinal hyperexcitability is sexually dimorphic. The lack of coupling of disinhibition to NMDAR potentiation suggests divergent neuronal signalling drives SDH hyperexcitability and chronic pain in females. This thesis highlights the importance of sex-inclusive research.






Carleton University

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