期刊
SCIENCE ADVANCES
卷 9, 期 13, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.ade9931
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Following peripheral nerve injury, activation of purinergic signaling, mediated by extracellular ATP release, is essential for microglia activation and neuropathic pain. However, the mechanisms of ATP release are not well-understood. This study identifies the volume-regulated anion channel (VRAC) as an ATP-releasing channel activated by the inflammatory mediator sphingosine-1-phosphate (S1P) in microglia. Knockout mice lacking the VRAC subunit Swell1 show reduced ATP release, decreased microgliosis, neuronal hyperactivity, and attenuated neuropathic pain behaviors. Additionally, a high-throughput screen identifies dicumarol as a novel and potent VRAC inhibitor, which can alleviate mechanical allodynia in nerve-injured mice. These findings establish ATP-releasing VRAC in microglia as a crucial determinant of neuropathic pain and a potential therapeutic target.
Following peripheral nerve injury, extracellular adenosine 5 '-triphosphate (ATP)-mediated purinergic signaling is crucial for spinal cord microglia activation and neuropathic pain. However, the mechanisms of ATP release remain poorly understood. Here, we show that volume-regulated anion channel (VRAC) is an ATP-releasing channel and is activated by inflammatory mediator sphingosine-1-phosphate (S1P) in microglia. Mice with mi-croglia-specific deletion of Swell1 (also known as Lrrc8a), a VRAC essential subunit, had reduced peripheral nerve injury-induced increase in extracellular ATP in spinal cord. The mutant mice also exhibited decreased spinal microgliosis, dorsal horn neuronal hyperactivity, and both evoked and spontaneous neuropathic pain- like behaviors. We further performed high-throughput screens and identified an FDA-approved drug dicumarol as a novel and potent VRAC inhibitor. Intrathecal administration of dicumarol alleviated nerve injury-induced mechanical allodynia in mice. Our findings suggest that ATP-releasing VRAC in microglia is a key spinal cord determinant of neuropathic pain and a potential therapeutic target for this debilitating disease.
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