{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T19:32:17Z","timestamp":1790105537115,"version":"4.0.1"},"reference-count":77,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"821","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2025,10,22]]},"abstract":"<jats:p>\n                    Amplification of nociceptive transmission due to aberrant\n                    <jats:italic toggle=\"yes\">N<\/jats:italic>\n                    -methyl-\n                    <jats:sc>d<\/jats:sc>\n                    -aspartate receptor (NMDAR) hyperactivity in the spinal cord is a key characteristic of neuropathic pain. However, under normal conditions, both presynaptic and postsynaptic NMDARs in the spinal dorsal horn are largely inactive. The mechanisms restraining synaptic NMDAR activity remain enigmatic. Leucine-rich repeat-containing protein 8A (LRRC8A or SWELL1) is an essential component of volume-regulated anion channels typically involved in regulating cell volume. Here, we report that LRRC8A was highly expressed in dorsal root ganglion (DRG) and spinal dorsal horn neurons of rats. Nerve injury persistently reduced LRRC8A expression in the DRG. siRNA-mediated\n                    <jats:italic toggle=\"yes\">Lrrc8a<\/jats:italic>\n                    knockdown in rats or conditional\n                    <jats:italic toggle=\"yes\">Lrrc8a<\/jats:italic>\n                    knockout in DRG neurons in mice consistently caused a pain hypersensitivity phenotype that was readily reversed by NMDAR antagonists. Correspondingly,\n                    <jats:italic toggle=\"yes\">Lrrc8a<\/jats:italic>\n                    knockdown or conditional\n                    <jats:italic toggle=\"yes\">Lrrc8a<\/jats:italic>\n                    knockout in DRG neurons markedly augmented synaptic localization and activity of NMDARs in the spinal cord. LRRC8A interacted with NMDARs in both rat and human spinal cord tissues primarily through its C-terminal LRR domain, restricting the synaptic trafficking and activity of NMDARs. Furthermore,\n                    <jats:italic toggle=\"yes\">\n                      Lrrc8a\n                      <jats:sup>ebo\/ebo<\/jats:sup>\n                    <\/jats:italic>\n                    mutant mice, which lack the LRR domain, exhibited NMDAR-dependent pain hypersensitivity and synaptic NMDAR hyperactivity in the spinal cord. Additionally, intrathecal\n                    <jats:italic toggle=\"yes\">Lrrc8a<\/jats:italic>\n                    gene delivery eliminated nerve injury\u2013induced pain hypersensitivity and synaptic NMDAR hyperactivity in rats. These findings reveal that LRRC8A physically interacts with NMDARs and constitutively restricts their synaptic expression in the spinal cord. Reduced LRRC8A-NMDAR interactions increase synaptic expression of \u201cunleashed\u201d NMDARs, contributing to NMDAR hyperactivity and neuropathic pain in rodent models.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adu4879","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T17:59:08Z","timestamp":1761155948000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["LRRC8A constitutively inhibits pain hypersensitivity in rodent models by restraining NMDA receptor activity at spinal cord synapses"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3558-1314","authenticated-orcid":true,"given":"Meichun","family":"Deng","sequence":"first","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0426-8202","authenticated-orcid":true,"given":"Shao-Rui","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-Hua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1641-8650","authenticated-orcid":true,"given":"Jixiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuying","family":"Huang","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Benavides","sequence":"additional","affiliation":[{"name":"Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1092-1244","authenticated-orcid":true,"given":"Rajan","family":"Sah","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8444-3770","authenticated-orcid":true,"given":"Hui-Lin","family":"Pan","sequence":"additional","affiliation":[{"name":"Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, 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