Involvement of CaMKIIα in Multiple Sclerosis‐Associated Pain

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, with manifestations of neuroinflammation and demyelination. Pain in MS patients, with remarkable prevalence up to ~90%, significantly reduce quality of life. Over past decades, advances have been made in understanding the neurobiological mechanisms of motor dysfunction in MS, but to a much lesser extent, MS-associated pain. In this study, we tested the hypothesis that Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) plays a critical role in the development and maintenance of pain and neuropathy in MS. We established a widely used animal model, experimental autoimmune encephalomyelitis (EAE), to study the pain mechanism in mice. We found that spinal CaMKIIα activities were increased, correlating with the development of mechanical allodynia and thermal hyperalgesia, in EAE mice. Prophylactic and acute administration of KN93, an inhibitor of CaMKII, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE mice. Moreover, siRNA targeting CaMKIIα was effective in reversing established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIαT286A point-mutation mice showed significantly reduced signs of disease and pain severity when compared with littermate wildtype mice. Taken together, these data implicate a critical role of CaMKIIα as a cellular mechanism in pain and neuropathy in multiple sclerosis. Inhibiting CaMKIIα may offer potentially new pharmacological interventions to prevent or attenuate multiple sclerosis-associated pain.