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Here, we assessed the analgesic activity of N-acetylcysteine in the streptozotocin model of painful diabetic neuropathy and examined the effect of N-acetylcysteine on proteins that are involved in mechanisms of nociceptive sensitization. Mice with blood glucose levels \u2265250\u2009mg\/dl in response to a single intraperitoneal (i.p.) injection of streptozotocin (200\u2009mg\/kg) were used for the assessment of mechanical pain thresholds. Systemic treatment with N-acetylcysteine (100\u2009mg\/kg, i.p., either single injection or daily injections for seven\u2009days) caused analgesia in diabetic mice. N-acetylcysteine-induced analgesia was abrogated by the [Formula: see text] inhibitors, sulfasalazine (8\u2009mg\/kg, i.p.), erastin (30\u2009mg\/kg, i.p.), and sorafenib (10\u2009mg\/kg, i.p.), or by the mGlu2\/3 receptor antagonist, LY341495 (1\u2009mg\/kg, i.p.). Repeated administrations of N-acetylcysteine in diabetic mice reduced ERK1\/2 phosphorylation in the dorsal region of the lumbar spinal cord. The analgesic activity of N-acetylcysteine was occluded by the MEK inhibitor, PD0325901 (25\u2009mg\/kg, i.p.), the TRPV1 channel blocker, capsazepine (40\u2009mg\/kg, i.p.), or by a cocktail of NMDA and mGlu5 metabotropic glutamate receptor antagonists (memantine, 25\u2009mg\/kg, plus MTEP, 5\u2009mg\/kg, both i.p.). These findings offer the first demonstration that N-acetylcysteine relieves pain associated with diabetic neuropathy and holds promise for the use of N-acetylcysteine as an add-on drug in diabetic patients.<\/jats:p>","DOI":"10.1177\/1744806920904292","type":"journal-article","created":{"date-parts":[[2020,2,3]],"date-time":"2020-02-03T06:18:49Z","timestamp":1580710729000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":25,"title":["N-Acetylcysteine causes analgesia in a mouse model of painful diabetic neuropathy"],"prefix":"10.1177","volume":"16","author":[{"given":"Serena","family":"Notartomaso","sequence":"first","affiliation":[{"name":"IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela","family":"Scarselli","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Neurologico Mediterraneo Neuromed, Pozzilli, 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