{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T00:57:10Z","timestamp":1793321830909,"version":"4.5.0"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"23","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["2136\/20"],"award-info":[{"award-number":["2136\/20"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1202\/23"],"award-info":[{"award-number":["1202\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001698","name":"Israel Cancer Research Fund","doi-asserted-by":"publisher","award":["22-402-QOL"],"award-info":[{"award-number":["22-402-QOL"]}],"id":[{"id":"10.13039\/100001698","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,10]]},"abstract":"<jats:p>\n                    Paracetamol has been used for decades to relieve mild-to-moderate pain. Its analgesic effect is mainly attributed to its metabolite, AM404, acting on cannabinoid receptors or TRPV1 channels in central nervous system (CNS) neurons. Here, we show that AM404 is produced by primary sensory neurons. It inhibits sodium current in nociceptor neurons, blocking action potential (AP) generation and reducing nocifensive behavior in na\u00efve and inflamed rats. We demonstrated that this analgesic effect of AM404 is mediated by its direct inhibition of nociceptive voltage-gated sodium channels (Na\n                    <jats:sub>V<\/jats:sub>\n                    ) 1.8 and 1.7 via the local anesthetic binding site. The Na\n                    <jats:sub>V<\/jats:sub>\n                    1.8 and 1.7 inhibition was specific for AM404 and not observed with other metabolites of paracetamol. Our findings suggest that the analgesic effect of paracetamol is mediated mainly by direct AM404-induced inhibition of nociceptive sodium channels at the peripheral nociceptor neurons. Our findings lay a foundation for the potential development of AM404 as a selective local analgesic.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2413811122","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T13:34:46Z","timestamp":1749044086000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4079-5218","authenticated-orcid":false,"given":"Yossef","family":"Maatuf","sequence":"first","affiliation":[{"name":"The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5245-9083","authenticated-orcid":false,"given":"Yishai","family":"Kushnir","sequence":"additional","affiliation":[{"name":"Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]},{"name":"The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Nemirovski","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Unit, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7005-1143","authenticated-orcid":false,"given":"Mariana","family":"Ghantous","sequence":"additional","affiliation":[{"name":"The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5205-3709","authenticated-orcid":false,"given":"Ariel","family":"Iskimov","sequence":"additional","affiliation":[{"name":"The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3620-8116","authenticated-orcid":false,"given":"Alexander M.","family":"Binshtok","sequence":"additional","affiliation":[{"name":"Department of Medical Neurobiology, Institute for Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]},{"name":"The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6105-5035","authenticated-orcid":false,"given":"Avi","family":"Priel","sequence":"additional","affiliation":[{"name":"The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem","place":["Jerusalem, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1527-3458.2006.00250.x"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.580289"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10153420"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13656"},{"key":"e_1_3_4_5_2","first-page":"11","article-title":"Paracetamol: Mechanism of action, applications and safety concern","volume":"71","author":"Jozwiak-Bebenista M.","year":"2014","unstructured":"M. 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