title: Inhibition of DOR prevents remifentanil induced postoperative hyperalgesia through regulating the trafficking and function of spinal NMDA receptors in vivo and in vitro.
abstract: BACKGROUND
  Several studies have demonstrated that intraoperative remifentanil infusions have been associated with opioid-induced hyperalgesia (OIH). Activation of delta opioid receptor (DOR) and augmentation of N-methyl-d-aspartate (NMDA) receptor expression and function may play an important role in the development of OIH. The aim of this study was to investigate whether DOR inhibition could prevent remifentanil-induced hyperalgesia via regulating spinal NMDA receptor expression and function in vivo and in vitro.
  
  
  METHODS
  A rat model of remifentanil-induced postoperative hyperalgesia was performed with the DOR agonist deltorphin-deltorphin II or the DOR antagonist naltrindole injected intrathecally 10 min before remifentanil infusion. Mechanical and thermal hyperalgesia were measured at -24h, 2, 6, 24 and 48 h after remifentanil infusion. Western blot was applied to detect the membrane and total expression of DOR and NMDA receptor subunits (NR1, NR2A and NR2B) in spinal cord L4-L6 segments. In addition, whole-cell patch-clamp recording was used to investigate the effect of DOR inhibition on NMDA receptor-induced current in spinal cord slices in vitro.
  
  
  RESULTS
  We found that membrane trafficking of DOR, NR1 and NR2B subunits in the spinal cord increased after remifentanil administration and surgery. The DOR antagonist naltrindole could attenuate mechanical and thermal hyperalgesia without affecting baseline nociceptive threshold, reduce membrane expression of DOR and decrease the membrane and total expressions of NR1 and NR2B subunits. Furthermore, the amplitude and the frequency of NMDA receptor-induced current were significantly increased by remifentanil incubation in neurons of the dorsal horn, which was reversed by the application of naltrindole.
  
  
  CONCLUSIONS
  The above results indicate that inhibition of DOR could significantly inhibit remifentanil-induced hyperalgesia via modulating the total protein level, membrane trafficking and function of NMDA receptors in the dorsal horn of spinal cord, suggesting that naltrindole could be a potential anti-hyperalgesic agent for treating OIH.
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: 0208wcy@163.com.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: lisaliyize@126.com.
authors.forename: Yize
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: wanghaiyunmazui@126.com.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: xiekeliangmazui@126.com.
authors.forename: Keliang
authors.initials: K
authors.lastname: Xie
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: shuruichenmazui@163.com.
authors.forename: Ruichen
authors.initials: R
authors.lastname: Shu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: zhanglinlinmazui@163.com.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: hunanmazui@126.com.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: yuyonghaomazui@163.com.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Tianjin Medical University General Hospital, Tianjin 300052, PR China; Tianjin Research Institute of Anesthesiology, Tianjin 300052, PR China. Electronic address: tougaomazui@163.com.
authors.forename: Guolin
authors.initials: G
authors.lastname: Wang
mesh_terms: D018686:Anesthetics, Intravenous / Q000627:therapeutic use / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D006358:Hot Temperature; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D008159:Lumbar Vertebrae; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D010149:Postoperative Pain / Q000139:chemically induced / Q000517:prevention & control*; D010880:Piperidines / Q000627:therapeutic use / Q000633:toxicity*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077208:Remifentanil; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D046509:Tissue Culture Techniques; D014110:Touch
chemical_list: D018686:Anesthetics, Intravenous; D009292:Narcotic Antagonists; D009842:Oligopeptides; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017465:Receptors, Opioid, delta; C059567:deltorphin; C060209:deltorphin II, Ala(2)-; D009271:Naltrexone; C055382:naltrindole; D000077208:Remifentanil
keywords: Delta opioid receptor; Miniature excitatory postsynaptic current; N-methyl-d-aspartate receptor; Opioid-induced hyperalgesia