ATP-releasing SWELL1 channel in spinal microglia contributes to neuropathic pain

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.

Automated summary

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.