The Postgraduate Training Base of Jinzhou Medical University, Beijing, China.
Department of Anesthesiology, The PLA Rocket Force Characteristic Medical Center, Beijing, China.
Sleep. 2023 Nov 8;46(11). doi: 10.1093/sleep/zsad039.
This study verified that sleep deprivation before and after skin/muscle incision and retraction (SMIR) surgery increased the risk of chronic pain and investigated the underlying roles of microglial voltage-dependent anion channel 1 (VDAC1) signaling.
Adult mice received 6 hours of total sleep deprivation from 1 day prior to SMIR until the third day after surgery. Mechanical and heat-evoked pain was assessed before and within 21 days after surgery. Microglial activation and changes in VDAC1 expression and oligomerization were measured. Minocycline was injected to observe the effects of inhibiting microglial activation on pain maintenance. The VDAC1 inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) and oligomerization inhibitor VBIT-4 were used to determine the roles of VDAC1 signaling on microglial adenosine 5' triphosphate (ATP) release, inflammation (IL-1β and CCL2), and chronicity of pain.
Sleep deprivation significantly increased the pain duration after SMIR surgery, activated microglia, and enhanced VDAC1 signaling in the spinal cord. Minocycline inhibited microglial activation and alleviated sleep deprivation-induced pain maintenance. Lipopolysaccharide (LPS)-induced microglial activation was accompanied by increased VDAC1 expression and oligomerization, and more VDAC1 was observed on the cell membrane surface compared with control. DIDS and VBIT-4 rescued LPS-induced microglial ATP release and IL-1β and CCL2 expression. DIDS and VBIT-4 reversed sleep loss-induced microglial activation and pain chronicity in mice, similar to the effects of minocycline. No synergistic effects were found for minocycline plus VBIT-4 or DIDS.
Perioperative sleep deprivation activated spinal microglia and increases the risk of chronic postsurgical pain in mice. VDAC1 signaling regulates microglial activation-related ATP release, inflammation, and chronicity of pain.
本研究验证了皮肤/肌肉切开和牵开术（SMIR）前后的睡眠剥夺增加了慢性疼痛的风险，并探讨了小胶质细胞电压依赖性阴离子通道 1（VDAC1）信号的潜在作用。
成年小鼠在 SMIR 前一天至手术后第三天接受 6 小时的总睡眠剥夺。在手术前和手术后 21 天内评估机械和热诱发痛。测量小胶质细胞的激活以及 VDAC1 表达和寡聚化的变化。注射米诺环素以观察抑制小胶质细胞激活对疼痛维持的影响。使用 VDAC1 抑制剂 4,4'-二异硫氰基二苯乙烯-2,2'-二磺酸（DIDS）和寡聚化抑制剂 VBIT-4 来确定 VDAC1 信号在小胶质细胞三磷酸腺苷（ATP）释放、炎症（IL-1β和 CCL2）和疼痛慢性化中的作用。
睡眠剥夺显著增加了 SMIR 手术后的疼痛持续时间，激活了小胶质细胞，并增强了脊髓中的 VDAC1 信号。米诺环素抑制了小胶质细胞的激活，并减轻了睡眠剥夺引起的疼痛维持。脂多糖（LPS）诱导的小胶质细胞激活伴随着 VDAC1 表达和寡聚化的增加，与对照组相比，更多的 VDAC1 出现在细胞膜表面。DIDS 和 VBIT-4 挽救了 LPS 诱导的小胶质细胞 ATP 释放以及 IL-1β和 CCL2 的表达。DIDS 和 VBIT-4 逆转了睡眠剥夺诱导的小胶质细胞激活和小鼠疼痛慢性化，与米诺环素的作用相似。米诺环素加 VBIT-4 或 DIDS 之间没有协同作用。
围手术期睡眠剥夺激活了脊髓小胶质细胞，并增加了小鼠慢性手术后疼痛的风险。VDAC1 信号调节小胶质细胞激活相关的 ATP 释放、炎症和疼痛的慢性。
