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pISSN 2005-9159
eISSN 2093-0569

Experimental Research Article

Korean J Pain 2023; 36(3): 316-327

Published online July 1, 2023 https://doi.org/10.3344/kjp.22398

Copyright © The Korean Pain Society.

Antisense oligodeoxynucleotides against dynamin-related protein 1 reduce remifentanil-induced hyperalgesia by modulating spinal N-methyl-D-aspartate receptor expression in rats

Songyi Zhou1 , Yizhao Pan1 , Yan Zhang2 , Lijun Gu1 , Leikai Ma1 , Qingqing Xu2 , Weijian Wang1 , Jiehao Sun1

1Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
2Operative Room Nursing, 1st Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China

Correspondence to:Jiehao Sun
Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University, Fanhaixi road 1, Wenzhou, Zhejiang 325000, China
Tel: +86-13676721930, Fax: +86-13676721930, E-mail: sun_jiehao88@126.com

Weijian Wang
Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University, Fanhaixi road 1, Wenzhou, Zhejiang 325000, China
Tel: +86-13806683232, Fax: +86-13806683232, E-mail: wangwj2002@hotmail.com

*These authors contributed equally to this work.

Received: December 2, 2022; Revised: February 19, 2023; Accepted: April 2, 2023

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Spinal N-methyl-D-aspartate (NMDA) receptor activation is attributed to remifentanil-induced hyperalgesia (RIH). However, the specific mechanism and subsequent treatment is still unknown. Previous studies have shown that the dynamin-related protein 1 (DRP1)-mitochondria-reactive oxygen species (ROS) pathway plays an important role in neuropathic pain. This study examined whether antisense oligodeoxynucleotides against DRP1 (AS-DRP1) could reverse RIH.
Methods: The authors first measured changes in paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) at 24 hours before remifentanil infusion and 4, 8, 24, and 48 hours after infusion. The expression levels of DRP1 and NR2B were measured after behavioral testing using Western blotting. In addition, DRP1 expression was knocked down by intrathecal administration of AS-DRP1 to investigate the effects of DRP1 on RIH. The behavioral testing, the expression levels of spinal DRP1 and NR2B, and dorsal mitochondrial superoxide were measured. Changes in mitochondrial morphology were assessed using electron microscopy.
Results: After remifentanil exposure, upregulation of spinal DRP1 and NR2B was observed along with a reduction in PWMT and PWTL. In addition, AS-DRP1 improved RIH-induced PWTL and PWMT (P < 0.001 and P < 0.001) and reduced remifentanil-mediated enhancement of spinal DRP1 and NR2B expression (P = 0.020 and P = 0.022). More importantly, AS-DRP1 reversed RIH-induced mitochondrial fission (P = 0.020) and mitochondrial superoxide upregulation (P = 0.031).
Conclusions: These results indicate that AS-DRP1 could modulate NMDA receptor expression to prevent RIH through the DRP1-mitochondria-ROS pathway.

Keywords: Analgesia, Dynamins, Hyperalgesia, Mitochondria, Neuralgia, Oligodeoxyribonucleotides, Reactive Oxygen Species, Receptors, N-Methyl-D-Aspartate, Remifentanil, Superoxides.