Citation

* Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation, degeneration and demyelinating lesions within the central nervous system. Chronic pain is a highly prevalent symptom associated with MS, affecting 50-80% of patients over the course of their disease. Unfortunately, MS-related pain responds poorly to classical analgesics, contributing to overall disease burden and reduced quality of life. Despite the high incidence of chronic pain in MS, the underlying mechanisms remain poorly understood. The amygdala is a small nucleus within the limbic brain that is well-known for its role in integrating emotional and sensory information. The central nucleus of the amygdala, in particular, has recently emerged as an important brain center for pain modulation. Several chronic pain conditions are associated with alterations in amygdala neurocircuitry and anatomy, suggesting that these maladaptive changes contribute to pathological pain. This thesis focuses on elucidating the role of the central amygdala in the pathophysiology of pain in MS. I employed the myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE) model of MS in male and female C57BL/6 mice. Prior to the onset of clinical symptoms (pre-symptomatic phase), I assessed thermal pain hypersensitivity and opioid-induced analgesia with the tail withdrawal assay, and morphine reward with the conditioned place preference paradigm. Brain and spinal cord tissue were extracted on day of disease onset and prepared for immunohistochemical staining or fluorescent in situ hybridization. In the early stages of disease, male and female EAE mice exhibited robust microglial activation in the central amygdala, which was associated with heat hyperalgesia, impaired morphine reward and loss of morphine antinociception in females. EAE animals also displayed a lack of responsivity within the antinociceptive somatostatin-expressing neurons in the central amygdala. Induction of focal microglial activation in naïve mice via bilateral stereotactic microinjection of lipopolysaccharide into the central amygdala attenuated morphine analgesia in females, similar to that observed in EAE animals. Collectively, my data indicate that activated microglia within the central nucleus of the amygdala contribute to the sexually dimorphic effects of morphine and drive neuronal adaptations that lead to pain hypersensitivity in EAE. Therefore, novel approaches to treating pain in MS must take the effects of sex on pain regulation and treatment outcomes into consideration. My work further suggests that inhibiting microglial activation and restoring nociceptive signaling are potential strategies for improving pain management and analgesic efficacy in this patient population.