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Xenon ameliorates chronic post-surgical pain by regulating mitophagy in microglia and rats mediated by PINK1/Parkin
Hu Lv1,2, Jiaojiao Huang1,2, Xin Zhang1,2
1Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
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.
Insights
Xenon (Xe) inhalation alleviates chronic post-surgical pain (CPSP) by reducing spinal cord microglial activation and oxidative stress. This effect is mediated through the PINK1/Parkin pathway, promoting microglial mitophagy.
Area of Science:
- Neuroscience
- Anesthesiology
- Pain Management
Background:
- Chronic post-surgical pain (CPSP) significantly impacts patient recovery.
- Microglial activation in the spinal cord is a key factor in CPSP development and maintenance.
- The precise mechanism by which xenon (Xe), an anesthetic gas, modulates microglial activity in CPSP is not fully understood.
Purpose of the Study:
- To investigate the therapeutic potential of xenon in a rat model of chronic post-surgical pain (CPSP).
- To elucidate the underlying mechanisms of xenon's action, focusing on microglial activation, oxidative stress, and mitophagy.
- To explore the role of the PINK1/Parkin signaling pathway in xenon's analgesic effects.
Main Methods:
- Establishment of a CPSP rat model using skin/muscle incision and retraction (SMIR).
- Treatment with 50% xenon (Xe) inhalation for 1 hour daily for 5 consecutive days.
- Assessment of pain behaviors (PWMT, TWL), microglial activation (Iba1), oxidative stress markers (MDA, SOD, H2O2, CAT), mitophagy markers (Mito-Tracker, LC3), and the PINK1/Parkin pathway.
Main Results:
- Xenon treatment significantly improved pain behaviors (PWMT and TWL) in the CPSP rat model.
- Xe inhalation reduced microglial activation and oxidative stress in the spinal dorsal horn.
- Xe promoted microglial mitophagy and activated the PINK1/Parkin signaling pathway, as evidenced by increased autophagy markers and protein expression.
Conclusions:
- Xenon effectively ameliorates chronic post-surgical pain in rats.
- The analgesic effects of xenon are attributed to the regulation of microglial mitophagy via the PINK1/Parkin pathway.
- Xenon presents a promising therapeutic target for preventing and treating CPSP.
