Prevention of Remifentanil Induced Postoperative Hyperalgesia by Dexmedetomidine via Regulating the Trafficking and Function of Spinal NMDA Receptors as well as PKC and CaMKII Level In Vivo and In Vitro.
Remifentanil-induced secondary hyperalgesia has been demonstrated in both animal experiments and clinical trials. Enhancement of N-methyl-D-aspartate (NMDA) receptor trafficking as well as protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMKII) have been reported to be involved in the induction and maintenance of central sensitization. In the current study, it was demonstrated that dexmedetomidine could prevent remifentanil-induced hyperalgesia (RIH) via regulating spinal NMDAR-PKC-Ca2+/ CaMKII pathway in vivo and in vitro. We firstly investigated the effect of dexmedetomidine, a highly selective α2-adrenergic receptor agonist, on mechanical and thermal hyperalgesia using a rat model of RIH. NMDA receptor subunits (NR1, NR2A and NR2B) expression and membrane trafficking as well as PKC and CaMKII expression in spinal cord L4-L5 segments were measured by Western blot analysis. The expression of NMDA receptor subunits (NR1, NR2A and NR2B) were also detected by immunohistochemistry. Further more, the effect of dexmedetomidine on NMDA receptor current amplitude and frequency in spinal cord slices were investigated by whole-cell patch-clamp recording. We found that remifentail infusion at 1.2 μg.kg-1.min-1 for 90 min caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate as well as increased PKC and CaMKII expression in spinal cord dorsal horn. Subcutaneously injection of dexmedetomidine at the dose of 50 μg/kg at 30 min before plantar incision significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate as well as increased PKC and CaMKII expression in spinal cord dorsal horn. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was dose-dependently attenuated by dexmedetomidine. These results suggest that dexmedetomidine can significantly ameliorate RIH via modulating the expression, membrane trafficking and function of NMDA receptors as well as PKC and CaMKII level in spinal dorsal horn, which present useful insights into the mechanistic action of dexmedetomidine as a potential anti-hyperalgesic agents for treating RIH.
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Yuan
Y
Yuan
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Zhe
Z
Sun
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Yi
Y
Chen
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Yuxin
Y
Zheng
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Ke-Liang
KL
Xie
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Ying
Y
He
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Zhifen
Z
Wang
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Guo-Lin
GL
Wang
Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin, China.|Tianjin Research Institute of Anesthesiology, Tianjin, China.
Yong-Hao
YH
Yu
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D018890:Chemoprevention; D020927:Dexmedetomidine / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D059408:Pain Management / Q000379:methods; D010149:Postoperative Pain / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects*; D011184:Postoperative Period; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D000077208:Remifentanil; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D020927:Dexmedetomidine; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D000077208:Remifentanil