Xenon ameliorates chronic post-surgical pain by regulating mitophagy in microglia and rats mediated by PINK1/Parkin pathway

Hu Lv; Jiaojiao Huang; Xin Zhang; Zhiyong He; Jun Zhang; Wei Chen

doi:10.7717/peerj.16855

Xenon ameliorates chronic post-surgical pain by regulating mitophagy in microglia and rats mediated by PINK1/Parkin pathway

PeerJ. 2024 Feb 19:12:e16855. doi: 10.7717/peerj.16855. eCollection 2024.

Authors

Hu Lv^#^{1

2}, Jiaojiao Huang^#^{1

2}, Xin Zhang^{1

2}, Zhiyong He^{1

2}, Jun Zhang^{1

2}, Wei Chen^{1

2}

Affiliations

¹ Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.

^# Contributed equally.

Abstract

Background: Chronic post-surgical pain (CPSP) is one of the important causes of poor postoperative outcomes, the activation of microglia in the spinal cord is closely related to the generation, transmission and maintenance of CPSP. Xenon (Xe), an anesthetic gas, has been reported to be able to significantly reduce intraoperative analgesia and postoperative pain sensation at low doses. However, the mechanism of the regulatory effect of xenon on activated microglia after CPSP remains unclear.

Methods: In this study, CPSP model rats were treated with 50% Xe inhalation for 1 h following skin/muscle incision and retraction (SMIR), once a day for 5 consecutive days, and then the painbehavioraltests (pain behavior indexes paw withdrawal mechanical threshold, PWMT and thermal withdrawal latency, TWL), microglial activation, oxidative stress-related indexes (malondialdehyde, MDA; superoxide dismutase, SOD; hydrogen peroxide, H₂O₂; and catalase, CAT), mitophagy and PINK1/Parkin pathway were examined.

Results: The present results showed that a single dose of Xe treatment in SMIR rat model could significantly improve PWMT and TWL in the short-term at a single treatment and long-term at multiple treatments. Xe treatment inhibited microglia activation and oxidative stress in the spinal dorsal horn of SMIR rats, as indicated by the decrease of Iba1 and MDA/H₂O₂ levels and the increase of SOD/CAT levels. Compared with the control group, Xe further increased the CPSP promoted Mito-Tracker (a mitochondrial marker) and LC3 (an autophagy marker) co-localization positive spots and PINK1/Parkin/ATG5/BECN1 (autophagy-related proteins) protein expression levels, and inhibited the Mito-SOX (a mitochondrial reactive oxygen species marker) positive signal, indicating that Xe promoted microglia mitophagy and inhibited oxidative stress in CPSP. Mechanistically, we verified that Xe promoted PINK1/Parkin signaling pathway activation.

Conclusion: Xe plays a role in ameliorating chronic post-surgical pain by regulating the PINK1/Parkin pathway mediated microglial mitophagy and provide new ideas and targets for the prevention and treatment of CPSP.

Keywords: Chronic post-surgical pain; Mitophagy; PINK1/Parkin pathway; Xenon.

MeSH terms

Animals
Hydrogen Peroxide / metabolism
Microglia* / metabolism
Mitophagy*
Pain, Postoperative / drug therapy
Protein Kinases / metabolism
Rats
Superoxide Dismutase / metabolism
Ubiquitin-Protein Ligases / metabolism
Xenon / pharmacology

Substances

Xenon
Hydrogen Peroxide
Superoxide Dismutase
Ubiquitin-Protein Ligases
Protein Kinases

Grants and funding

This work was supported by the Natural Science Foundation of Shanghai (No. 21ZR1414000). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.