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

Abstract

Following peripheral nerve injury, extracellular 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 microglia-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.

LRRC8/VRAC volume-regulated anion channels are crucial for hearing

“…We hypothesize that the downregulation of Kir4.1 is caused by the lack of a secreted factor, possibly glutathione that is normally transported through VRAC. This would be in line with an increasing number of reports showing the physiological importance of VRAC-mediated release of molecules as diverse as glutamate ( 37 ), GABA ( 68 , 69 ), ATP ( 69 ) and cGAMP ( 34 , 35 ). The wide expression pattern of VRAC in the inner ear, and the ability of VRACs to transport cisplatin ( 10 ), suggests that VRAC may also play a role in ototoxicity.…”

SHED-derived exosomes attenuate trigeminal neuralgia after CCI of the infraorbital nerve in mice via the miR-24-3p/IL-1R1/p-p38 MAPK pathway

“…High energy levels (including high glucose/glycogen, in ammation, etc.) are associated with reduced AMPK activation [51,52]. In recent decades, AMPK activated by various canonical/noncanonical regulation pathways has been regarded as a therapeutic target for NP [53].…”