Microglial voltage-dependent anion channel 1 signaling modulates sleep deprivation-induced transition to chronic postsurgical pain

Abstract

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.

Enriched environment ameliorates fear memory impairments induced by sleep deprivation via inhibiting PIEZO1/calpain/autophagy signaling pathway in the basal forebrain

“…Commencing with entry into the daytime cycle, mice were subjected to 6 h of complete sleep deprivation using a sleep deprivation apparatus in biofeedback mode (XR108S, Shanghai XinRuan Information Technology Co., Ltd.) 20 . The sleep deprivation efficiency of this apparatus has been previously validated 30 . During this process, mice moved naturally and had free access to food and water.…”

“… 20 The sleep deprivation efficiency of this apparatus has been previously validated. 30 During this process, mice moved naturally and had free access to food and water. The apparatus monitored the animal behaviors and activities, and when mice closed their eyes or stopped moving, the percussion bar started to rotate to disturb them and force them to stay awake.…”

“…20 The sleep deprivation efficiency of this apparatus has been previously validated. 30 During this process, mice moved naturally and had free access to food and water.…”

Associations between perioperative sleep patterns and clinical outcomes in patients with intracranial tumors: a correlation study

“…Different kinds of sleep disorders often lead to varied clinical complications and outcomes due to distinct internal pathophysiological mechanisms. It has been demonstrated that reduced sleep time could activate the microglial cells through microglial voltage-dependent anion channel 1 and increase the activity of L-type calcium channels, leading to increased post-operative pain ( 19 , 20 ). Obstructive sleep apnea syndrome is deeply associated with post-operative cognitive dysfunction, and the mechanisms involved include neuroinflammation, impairment of hippocampal synaptic plasticity, and blood–brain barrier dysfunction ( 21 – 23 ).…”