Liu Xiaojie, Liu Yue, Zhang Juan, Zhang Wei, Sun Yu-E, Gu Xiaoping, Ma Zhengliang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Brain Res Bull. 2014 Jul;106:9-16. doi: 10.1016/j.brainresbull.2014.04.008. Epub 2014 Apr 21.
N-methyl-D-aspartate receptor (NMDAR) and metabotropic glutamate receptor 5 (mGluR5) play an important role in nociceptive processing and central sensitization. Our previous study showed that tyrosine phosphorylation of NMDAR subunit 2B (NR2B) at Tyr1472 in spinal dorsal horn contributes to the postoperative hyperalgesia induced by remifentanil. Cyclin-dependent kinase 5 (Cdk5) has been implicated in synaptic plasticity, learning, memory and pain signaling via regulating the phosphorylation of NMDAR and mGluR5. In the present study, a rat model of postoperative pain was used to investigate the role of Cdk5 in spinal dorsal horn in remifentanil-induced hyperalgesia and the intervention of pretreatment with Cdk5 inhibitor roscovitine. Intraoperative infusion of remifentanil (0.04 mg/kg, subcutaneous) significantly enhanced mechanical allodynia and thermal hyperalgesia induced by plantar incision during the postoperative period (each lasting between 2 h and 48 h), which were attenuated by pretreatment with roscovitine. Correlated with the pain behavior changes, Western blotting revealed that there was a significant increase in the expression of Cdk5 and its activator p35/p25, and further the kinase activity of Cdk5 in spinal dorsal horn after intraoperative infusion of remifentanil. The phosphorylation of NR2A at Ser1232, the phosphorylation of NR2B at Tyr1472 and the phosphorylation of mGluR5 at Ser1167 were also significantly up-regulated. Furthermore, these increases were attenuated by pretreatment with roscovitine. These results suggested that Cdk5 may contribute to remifentanil-induced postoperative hyperalgesia via regulating the phosphorylation of NMDAR and mGluR5 in spinal dorsal horn. These findings provide experimental evidence for the further application of Cdk5 inhibitor in preventing remifentanil-induced hyperalgesia.
N-甲基-D-天冬氨酸受体（NMDAR）和代谢型谷氨酸受体5（mGluR5）在伤害性感受处理和中枢敏化中起重要作用。我们之前的研究表明，脊髓背角中NMDAR亚基2B（NR2B）的酪氨酸1472位点磷酸化促成了瑞芬太尼诱导的术后痛觉过敏。细胞周期蛋白依赖性激酶5（Cdk5）通过调节NMDAR和mGluR5的磷酸化参与突触可塑性、学习、记忆和疼痛信号传导。在本研究中，使用大鼠术后疼痛模型来研究脊髓背角中Cdk5在瑞芬太尼诱导的痛觉过敏中的作用以及Cdk5抑制剂roscovitine预处理的干预作用。术中输注瑞芬太尼（0.04 mg/kg，皮下注射）显著增强了术后期间足底切口诱导的机械性异常性疼痛和热痛觉过敏（每次持续2小时至48小时），而roscovitine预处理可减轻这些症状。与疼痛行为变化相关，蛋白质印迹法显示，术中输注瑞芬太尼后，脊髓背角中Cdk5及其激活剂p35/p25的表达显著增加，并且Cdk5的激酶活性进一步增强。NR2A的丝氨酸1232位点磷酸化、NR2B的酪氨酸1472位点磷酸化以及mGluR5的丝氨酸1167位点磷酸化也显著上调。此外，这些增加被roscovitine预处理所减弱。这些结果表明，Cdk5可能通过调节脊髓背角中NMDAR和mGluR5的磷酸化促成瑞芬太尼诱导的术后痛觉过敏。这些发现为Cdk5抑制剂在预防瑞芬太尼诱导的痛觉过敏中的进一步应用提供了实验证据。
