The Korean Journal of Pain

The Korean Pain Society (대한통증학회)
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Antisense oligodeoxynucleotides against dynamin-related protein 1 reduce remifentanil-induced hyperalgesia by modulating spinal N-methyl-D-aspartate receptor expression in rats

  • Songyi Zhou (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Yizhao Pan (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Yan Zhang (Operative Room Nursing, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Lijun Gu (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Leikai Ma (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Qingqing Xu (Operative Room Nursing, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Weijian Wang (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University) ;
  • Jiehao Sun (Department of Anesthesiology, 1st Affiliated Hospital, Wenzhou Medical University)
  • Received : 2022.12.02
  • Accepted : 2023.04.02
  • Published : 2023.07.01
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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

Acknowledgement

The authors thank Dr. Fangfang Liu at Peking University for statistical assistance.

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