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.

CONCLUSION:

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: Chunyan Wang, Yize Li, Haiyun Wang, Keliang Xie, Ruichen Shu, Linlin Zhang, Nan Hu, Yonghao Yu, Guolin Wang
• Journal: Brain research bulletin (Brain Res Bull) Vol. 110 Pg. 30-9 (Jan 2015) ISSN: 1873-2747 [Electronic] United States
• PMID: 25498394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• Anesthetics, Intravenous
• Narcotic Antagonists
• Oligopeptides
• Piperidines
• Receptors, N-Methyl-D-Aspartate
• Receptors, Opioid, delta
• deltorphin
• deltorphin II, Ala(2)-
• Naltrexone
• naltrindole
• Remifentanil

Topics

• Anesthetics, Intravenous (therapeutic use, toxicity)
• Animals
• Disease Models, Animal
• Hot Temperature
• Hyperalgesia (chemically induced, metabolism, prevention & control)
• Lumbar Vertebrae
• Male
• Naltrexone (analogs & derivatives, pharmacology)
• Narcotic Antagonists (pharmacology)
• Oligopeptides (pharmacology)
• Pain Threshold (drug effects, physiology)
• Pain, Postoperative (chemically induced, prevention & control)
• Piperidines (therapeutic use, toxicity)
• Posterior Horn Cells (drug effects, metabolism)
• Random Allocation
• Rats, Sprague-Dawley
• Receptors, N-Methyl-D-Aspartate (metabolism)
• Receptors, Opioid, delta (agonists, antagonists & inhibitors, metabolism)
• Remifentanil
• Spinal Cord (drug effects, metabolism)
• Tissue Culture Techniques
• Touch