伪₂ noradrenergic receptor suppressed CaMKII signaling in spinal dorsal horn of mice with inflammatory pain

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• 作者：Xin-Tai Wang ; Xia Lian ; Ying-Ming Xu ; Zhan-Wei Suo ; Xian Yang ; Xiao-Dong Hu
• 关键词：伪2 noradrenergic receptor ; Inflammatory pain ; Calcium/calmodulin-dependent protein kinase II ; N-methyl-d-aspartate receptor ; 伪-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor
• 刊名：European Journal of Pharmacology
• 出版年：5 February, 2014
• 年：2014
• 卷：724
• 期：Complete
• 页码：16-23
• 全文大小：6247 K

文摘

Intrathecal application of 伪₂ noradrenergic receptor agonists effectively alleviates the pathological pain induced by peripheral tissue injury. However, the spinal antinociceptive mechanisms of 伪₂ noradrenergic receptors remain to be characterized. The present study performed immunohistochemistry and western blot to elucidate the signaling pathway initiated by 伪₂ noradrenergic receptors in spinal dorsal horn of mice, and identified calcium/calmodulin-dependent protein kinase II (CaMKII) as an important target for noradrenergic suppression of inflammatory pain. Our data showed that intraplantar injection of Complete Freund's Adjuvant (CFA) substantially enhanced CaMKII autophosphorylation at Threonine 286, which could be abolished by intrathecal administration of 伪₂ noradrenergic receptor agonist clonidine. Gi protein-coupled 伪₂ noradrenergic receptor might inhibit cAMP-dependent protein kinase (PKA) to disturb CaMKII signaling. We found that pharmacological activation of PKA in intact mice also enhanced spinal CaMKII autophosphorylation level, which was completely antagonized by clonidine. Moreover, direct PKA inhibition in CFA-injected mice mimicked the suppressive effect of 伪₂ noradrenergic receptors on CaMKII. PKA inhibition has been shown to downregulate CaMKII by enhancing protein phosphatase activity. Consistent with this notion, spinal treatment with protein phosphatase inhibitor okadaic acid ruled out clonidine-mediated CaMKII dephosphorylation in CFA-injected mice. Through PKA/protein phosphatase/CaMKII pathway, clonidine noticeably decreased CFA-evoked phosphorylation of N-methyl-d-aspartate subtype glutamate receptor GluN1 and GluN2B subunit as well as 伪-amino-3-hydroxy-5-methylisoxazole-4-propionic Acid subtype glutamate receptor GluA1 subunit. These data suggested that interference with CaMKII signaling might represent an important mechanism underlying noradrenergic suppression of inflammatory pain.