■慢性术后疼痛(CPSP)是术后不良结局的重要原因之一,脊髓小胶质细胞的激活与生成密切相关,CPSP的传输和维护。氙气(Xe),一种麻醉气体,据报道,低剂量能够显着降低术中镇痛和术后疼痛感觉。然而,氙气对CPSP后活化小胶质细胞的调控作用机制尚不清楚。
■在这项研究中,CPSP模型大鼠在皮肤/肌肉切开和缩回(SMIR)后,用50%Xe吸入治疗1小时,每天一次,连续5天,然后进行疼痛行为测试(疼痛行为指标爪退缩机械阈值,PWMT和热退出延迟,TWL),小胶质细胞激活,氧化应激相关指标(丙二醛,丙二醛;超氧化物歧化酶,SOD;过氧化氢,H2O2;和过氧化氢酶,CAT),检测线粒体自噬和PINK1/Parkin通路。
■目前的结果表明,在SMIR大鼠模型中,单剂量的Xe治疗可以在单次治疗的短期和多次治疗的长期显着改善PWMT和TWL。Xe处理抑制SMIR大鼠脊髓背角小胶质细胞活化和氧化应激,如Iba1和MDA/H2O2水平的降低和SOD/CAT水平的增加所表明的。与对照组相比,Xe进一步增加CPSP促进Mito-Tracker(一种线粒体标记物)和LC3(一种自噬标记物)共定位阳性斑点和PINK1/Parkin/ATG5/BECN1(自噬相关蛋白)蛋白表达水平,抑制线粒体活性氧标记物Mito-SOX阳性信号,表明Xe促进小胶质细胞线粒体自噬并抑制CPSP中的氧化应激。机械上,我们验证了Xe促进PINK1/Parkin信号通路的激活。
■Xe通过调节PINK1/Parkin通路介导的小胶质细胞线粒体自噬,在改善术后慢性疼痛中发挥作用,为CPSP的预防和治疗提供新的思路和靶点。
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.