The impact of morphine on nerve injury recovery and lipid metabolism pathways

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Neuropathic pain resulting from peripheral nerve injury is among the most debilitating types of chronic pain conditions. Opioid medications are often used despite their poor efficacy in treating neuropathic pain symptoms and concerns about adverse effects. Notably, emerging evidence suggests that rather than alleviating neuropathic pain, opioids may worsen mechanical allodynia, wherein innocuous stimuli elicit pain. Morphine has been shown to exacerbate nerve injury-induced mechanical allodynia, but the cause is not understood. Both morphine and nerve injury have been implicated in myelin and oligodendrocyte perturbations. As myelin is primarily composed of lipids, here I determined whether spinal lipid metabolism alterations are a potential mechanism underlying morphine exacerbated neuropathic pain. In this study, I characterized neuropathic pain development and recovery using the chronic constriction injury model (CCI), which results in robust mechanical allodynia. I demonstrated that delayed morphine treatment of CCI animals resulted in prolonged mechanical allodynia and recovery from nerve injury, as compared to nerve injured mice given saline. Using profiling arrays for cholesterol metabolism and lipoprotein signaling, I found that morphine further increases the CCI-induced lipid metabolism changes within the spinal cord. More specifically, I found that cholesterol metabolic and lipoprotein clearance pathways are upregulated in nerve injured animals given saline when earlier and later timepoints are compared, suggesting their role in recovery. Conversely, these same pathways are downregulated in morphine treated CCI animals. To confirm these results, I validated the six most dysregulated gene candidates and found that Cyp11a1 was significantly upregulated in CCI animals treated with morphine. These results suggest that morphine could be delaying recovery from CCI by dysregulating lipid metabolism at the spinal cord level. As glial cells are involved in lipid synthesis and maintenance of myelin, alterations in lipid metabolism could be linked to changes in oligodendrocytes, astrocytes, microglia, and myelination. These findings could help mitigate adverse opioid effects and improve treatment for people suffering from neuropathic pain.
Stokes-Heck, S. (2023). The impact of morphine on nerve injury recovery and lipid metabolism pathways (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from