{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T12:16:43Z","timestamp":1793276203562,"version":"4.5.0"},"reference-count":80,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"UK Medical research council","award":["MR\/V04077\/2"],"award-info":[{"award-number":["MR\/V04077\/2"]}],"id":[{"id":"https:\/\/ror.org\/03x94j517","id-type":"ROR","asserted-by":"crossref"}]},{"name":"BBSRC","award":["BB\/T01668X\/2"],"award-info":[{"award-number":["BB\/T01668X\/2"]}],"id":[{"id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Versus arthritis UK","award":["21971"],"award-info":[{"award-number":["21971"]}],"id":[{"id":"https:\/\/ror.org\/02jkpm469","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>\n                    Chronic pain results from maladaptive interaction between the immune and nervous systems. TRPM2 channels in immune cells (immune TRPM2) are believed to facilitate chronic pain by indirectly promoting immune-inflammatory responses, whereas TRPM2 in sensory neurons (neuronal TRPM2) acts as a warmth sensor critical to sense innocuous warm temperatures. However, neuronal TRPM2 mediates the warmth sensitivity of less than 3.5% of sensory neurons. The functions of the vast majority of TRPM2\n                    <jats:sup>+<\/jats:sup>\n                    neurons are unknown. Here, we show that neuronal TRPM2 functions as a pain sensor responsible for directly transducing acute and chronic pain independently of immune TRPM2. Both chronic arthritis pain and neuropathic pain were markedly reduced in TRPM2-knockout mice, and the pain deficit was recapitulated by sole deletion of neuronal TRPM2. However, immune and inflammatory responses were largely similar between wild-type and neuronal TRPM2-deficient mice. Moreover, antagonizing TRPM2 rapidly reversed arthritis pain and neuropathic pain. Notably, TRPM2 is activated by PGE2 and IgG immune complex (IgG-IC) through coupling to G\u03b1oA and Fc\u03b3RI, respectively, independently of conventional signaling messengers. Consistently, acute pain induced by PGE2 and IgG-IC was abolished in TRPM2 mutant mice. We conclude that neuronal TRPM2 is a convergent direct pain transducer independently of inflammation, representing an appealing target for alleviating chronic pain.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2532289123","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:37:27Z","timestamp":1789580247000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":1,"title":["TRPM2 is a direct pain transducer"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-5738-1883","authenticated-orcid":false,"given":"Linda","family":"Varghese","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01a77tt86","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Sciences, University of Warwick","place":["Coventry, United 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