Abstract
Pain is a common and severe symptom in multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the CNS. The neurobiological mechanism underlying MS pain is poorly understood. In this study, we investigated the role of Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα) in driving chronic pain in MS using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that spinal CaMKIIα activity was enhanced in EAE, correlating with the development of ongoing spontaneous pain and evoked hypersensitivity to mechanical and thermal stimuli. Prophylactic or acute administration of KN93, a CaMKIIα inhibitor, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE. siRNA targeting CaMKIIα reversed established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIαT286A point mutation mice showed significantly reduced EAE clinical scores, an absence of evoked pain, and ongoing spontaneous pain when compared with littermate wild-type mice. We found that IL-17 is responsible for inducing but not maintaining mechanical and thermal hyperalgesia that is mediated by CaMKIIα signaling in EAE. Together, these data implicate a critical role of CaMKIIα as a cellular mechanism for pain and neuropathy in multiple sclerosis and IL-17 may act upstream of CaMKIIα in the generation of pain.SIGNIFICANCE STATEMENT Pain is highly prevalent in patients with multiple sclerosis (MS), significantly reducing patients' quality of life. Using the experimental autoimmune encephalomyelitis (EAE) model, we were able to study not only evoked hyperalgesia, but also for the first time to demonstrate spontaneous pain that is also experienced by patients. Our study identified a role of spinal CaMKIIα in promoting and maintaining persistent ongoing spontaneous pain and evoked hyperalgesia pain in EAE. We further demonstrated that IL-17 contributes to persistent pain in EAE and functions as an upstream regulator of CaMKIIα signaling. These data for the first time implicated CaMKIIα and IL-17 as critical regulators of persistent pain in EAE, which may ultimately offer new therapeutic targets for mitigating pain in multiple sclerosis.