Microglial VDAC1 signaling modulates sleep deprivation-induced transition to chronic postsurgical pain

by Selleckchem | Apr 18 2023

Study objectives: 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 VDAC1 signaling.

Methods: Adult mice received six hours of total sleep deprivation from one day prior to SMIR until the third days after surgery. Mechanical and heat-evoked pain was assessed before and within 21 days after surgery. Microglial activation and changes of VDAC1 expression and oligomerization were measured. Minocycline was injected to observe the effects of inhibiting microglial activation on pain maintenance. The VDAC1 inhibitor DIDS and oligomerization inhibitor VBIT-4 were used to determine the roles of VDAC1 signaling on microglial ATP release, inflammation (IL-1β and CCL2), and chronicity of pain.

Results: 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.

Conclusions: 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.

Comments：

The study aimed to investigate the effects of sleep deprivation before and after SMIR surgery on chronic pain risk in mice and to explore the role of microglial VDAC1 signaling in this process. The researchers conducted experiments in which mice received sleep deprivation before and after surgery, and pain duration was measured. They also assessed microglial activation and changes in VDAC1 expression and oligomerization in the spinal cord. Minocycline was used to inhibit microglial activation, and DIDS and VBIT-4 were used to examine the effects of VDAC1 signaling on microglial ATP release, inflammation, and chronicity of pain.

The study found that sleep deprivation increased pain duration after SMIR surgery and activated microglia in the spinal cord. The researchers observed increased VDAC1 signaling in the spinal cord, which was associated with increased microglial ATP release and inflammation. Minocycline was effective in alleviating sleep deprivation-induced pain maintenance. Furthermore, the researchers found that inhibiting VDAC1 signaling using DIDS and VBIT-4 reversed the effects of sleep deprivation on microglial activation and pain chronicity in mice.

In conclusion, this study suggests that sleep deprivation before and after SMIR surgery increases the risk of chronic pain in mice by activating spinal microglia, and that VDAC1 signaling regulates microglial activation-related ATP release, inflammation, and chronicity of pain. These findings may provide a basis for developing interventions to prevent chronic pain in patients undergoing surgery, particularly those who experience sleep deprivation.