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

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 voltage-dependent anion channel 1 (VDAC1) signaling. METHODS: 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-1ß 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-1ß 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.

Neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.

FGF10 is a member of fibroblast growth factors (FGFs). We previously showed that FGF10 protects neuron against oxygen-glucose deprivation injury in vitro; however, the effect of FGF10 in ischemic stroke in vivo is unknown. In the present study, we showed that FGF10 was mainly expressed in neurons but not astrocytes, and detected FGF10 in mouse cerebrospinal fluid. The FGF10 levels in neurons culture medium and cell lysate were much higher than those in astrocytes. FGF10 expression in brain tissue and FGF10 level in CSF were increased in mouse middle cerebral artery occlusion (MCAO) model. Administration of FGF10 into lateral cerebroventricle not only decreased MCAO-induced brain infarct volume and neurological deficit, but also reduced the number of TUNEL-positive cells and activities of Caspases. Moreover, FGF10 treatment depressed the triggered inflammatory factors (TNF-α and IL-6) and NF-κB signaling pathway, and increased phosphorylation of PI3K/Akt signaling pathway. Blockade of PI3K/Akt signaling pathway by wortmannin and Akt1/2-kinase inhibitor, partly compromised the neuroprotection of FGF10. However, blockade of PI3K/Akt signaling pathway did not impair the anti-inflammation action of FGF10. Collectively, our results demonstrate that neuron-derived FGF10 ameliorates cerebral ischemia injury via inhibiting NF-κB-dependent neuroinflammation and activating PI3K/Akt survival signaling pathway in mice.