| First Author | Hu X | Year | 2018 |
| Journal | J Neurosci | Volume | 38 |
| Issue | 1 | Pages | 232-244 |
| PubMed ID | 29146590 | Mgi Jnum | J:256424 |
| Mgi Id | MGI:6108555 | Doi | 10.1523/JNEUROSCI.2666-17.2017 |
| Citation | Hu X, et al. (2018) CaMKIIalpha Mediates the Effect of IL-17 To Promote Ongoing Spontaneous and Evoked Pain in Multiple Sclerosis. J Neurosci 38(1):232-244 |
| abstractText | 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 IIalpha (CaMKIIalpha) in driving chronic pain in MS using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that spinal CaMKIIalpha 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 CaMKIIalpha inhibitor, significantly reduced the clinical scores of EAE and attenuated mechanical allodynia and thermal hyperalgesia in EAE. siRNA targeting CaMKIIalpha reversed established mechanical and thermal hypersensitivity in EAE mice. Furthermore, CaMKIIalphaT286A 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 CaMKIIalpha signaling in EAE. Together, these data implicate a critical role of CaMKIIalpha as a cellular mechanism for pain and neuropathy in multiple sclerosis and IL-17 may act upstream of CaMKIIalpha 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 CaMKIIalpha 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 CaMKIIalpha signaling. These data for the first time implicated CaMKIIalpha and IL-17 as critical regulators of persistent pain in EAE, which may ultimately offer new therapeutic targets for mitigating pain in multiple sclerosis. |
