Intrathecal administration of roscovitine prevents remifentanil-induced postoperative hyperalgesia and decreases the phosphorylation of N-methyl-D-aspartate receptor and metabotropic glutamate receptor 5 in spinal cord.
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.
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Xiaojie
X
Liu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Yue
Y
Liu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Juan
J
Zhang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Wei
W
Zhang
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China.
Yu-E
YE
Sun
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China. Electronic address: xiaopinggu1@gmail.com.
Xiaoping
X
Gu
Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China. Electronic address: mazhengliang1964@163.com.
Zhengliang
Z
Ma
D000701:Analgesics, Opioid / Q000633:toxicity*; D000818:Animals; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D007278:Injections, Spinal; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D010766:Phosphorylation; D010880:Piperidines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000077208:Remifentanil; D000077546:Roscovitine; D013116:Spinal Cord / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
D000701:Analgesics, Opioid; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011687:Purines; D064529:Receptor, Metabotropic Glutamate 5; D016194:Receptors, N-Methyl-D-Aspartate; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D000077208:Remifentanil
Cyclin-dependent kinase 5; Metabotropic glutamate receptor 5; N-methyl-d-aspartate receptor; Opioid-induced hyperalgesia; Remifentanil