Glycogen synthase kinase-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating N-methyl-D-aspartate receptor trafficking.

Abstract

BACKGROUND:

Although remifentanil provides perfect analgesia during surgery, postoperative hyperalgesia after remifentanil administration might be a challenge to anesthesiologists. The trafficking and activation of N-methyl-D-aspartate (NMDA) receptors have a pivotal role in the development and maintenance of remifentanil-induced postoperative hyperalgesia. However, the underlying mechanisms of hyperalgesia are poorly elucidated. We designed the present study to examine the hypothesis that glycogen synthase kinase (GSK)-3β could contribute to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor trafficking in the spinal cord.

METHODS:

Using a rat model of remifentanil-induced postoperative hyperalgesia, we first tested thermal and mechanical hyperalgesia at baseline (24 hours before incision) and 2, 6, 24, and 48 hours after remifentanil infusion. GSK-3β mRNA and protein expression and NMDA receptor subunits (NR1, NR2A, and NR2B) trafficking in the spinal cord L4-L6 segments were then measured using real-time polymerase chain reaction and Western blot analysis. Furthermore, we investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on remifentanil-induced postoperative hyperalgesia and NMDA receptor subunits trafficking.

RESULTS:

Remifentanil induced significant postoperative hyperalgesia, as indicated by increased paw withdrawal latencies and thresholds to thermal and mechanical stimulation, which were markedly improved by pretreatment with TDZD-8. Moreover, remifentanil infusion increased the expression of GSK-3β mRNA and protein as well as the GSK-3β activity in the spinal cord. More importantly, intraoperative infusion of remifentanil increased NMDA receptor subunits (NR1 and NR2B) trafficking from the intracellular pool to surface pool in the spinal cord, which was significantly attenuated by TDZD-8.

CONCLUSION:

The above results suggest that activation of GSK-3β contributes to remifentanil-induced postoperative hyperalgesia via regulating NMDA receptor subunits (NR1 and NR2B) trafficking in the spinal cord. Inhibition of GSK-3β may be an effective novel option for the treatment of remifentanil-induced postoperative hyperalgesia.

• Authors: Yuan Yuan, Jing-yao Wang, Fang Yuan, Ke-liang Xie, Yong-hao Yu, Guo-lin Wang
• Journal: Anesthesia and analgesia (Anesth Analg) Vol. 116 Issue 2 Pg. 473-81 (Feb 2013) ISSN: 1526-7598 [Electronic] United States
• PMID: 23267003 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione
• Analgesics, Opioid
• Piperidines
• RNA, Messenger
• Receptors, N-Methyl-D-Aspartate
• Thiadiazoles
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, rat
• Glycogen Synthase Kinase 3
• Remifentanil

Topics

• Analgesics, Opioid (adverse effects)
• Animals
• Blotting, Western
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, physiology)
• Glycogen Synthase Kinase 3 beta
• Hot Temperature
• Hyperalgesia (chemically induced, metabolism)
• Male
• Pain, Postoperative (chemically induced, metabolism)
• Physical Stimulation
• Piperidines (adverse effects)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Real-Time Polymerase Chain Reaction
• Receptors, N-Methyl-D-Aspartate (drug effects)
• Remifentanil
• Spinal Cord (drug effects, metabolism)
• Thiadiazoles (pharmacology)