{"doi":"10.1101/2023.01.08.523161","title":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":391615,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.956,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":332215,"name":"Junhua Yang","orcid":"0000-0003-4117-7569","position":1,"is_corresponding":false},{"id":913564,"name":"Yuan Zhou","orcid":"0000-0003-2892-0100","position":2,"is_corresponding":false},{"id":1025913,"name":"Jianan Chen","orcid":"0000-0002-4796-3918","position":3,"is_corresponding":false},{"id":884412,"name":"Kevin Hong Chen","orcid":"0000-0002-5421-1538","position":4,"is_corresponding":false},{"id":858874,"name":"Chi Zhang","orcid":"0000-0001-7306-2243","position":5,"is_corresponding":false},{"id":480944,"name":"Yi Cheng","orcid":"0000-0003-4412-4235","position":6,"is_corresponding":false},{"id":941216,"name":"Nicholas Koylass","orcid":"0000-0003-3078-1867","position":7,"is_corresponding":false},{"id":433834,"name":"Jun O. Liu","orcid":"0000-0003-3842-9841","position":8,"is_corresponding":false},{"id":317530,"name":"Yun Guan","orcid":"0000-0003-1321-6655","position":9,"is_corresponding":false},{"id":302485,"name":"Zhaozhu Qiu","orcid":"0000-0002-9122-6077","position":10,"is_corresponding":false},{"id":1164399,"name":"Jiachen Chu","orcid":"0000-0001-8206-1146","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T01:18:47.408273Z","pmid":"36712065","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}