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Herein, the entanglement of downstream signals and NO-cGMP-K\n                    <jats:sub>ATP<\/jats:sub>\n                    pathway of nicorandil mediated antinociception was investigated against neuropathic pain induced by chronic constriction injury of sciatic nerve (CCI) and formalin evoked inflammatory pain. Nicorandil (150\u00a0mg\/kg, twice, 2\u00a0h apart, PO) reversed mechanical and cold allodynia induced by CCI, reduced the licking time and number of flinches in formalin test. L-arginine (500\u00a0mg\/kg, I.P), N(\u03c9)-nitro-L-arginine methyl ester (L-NAME, 10\u00a0mg\/kg, I.P), methylene blue (10\u00a0mg\/kg, I.P), sildenafil (2.5\u00a0mg\/kg, I.P) and glibenclamide (5\u00a0mg\/kg, I.P) were tested 30\u00a0min before nicorandil. The inhibitory effect of nicorandil on mechanical and cold allodynia was partially attenuated by L-arginine, methylene blue and sildenafil. L-NAME but not glibenclamide, potentiated the antinociceptive action of nicorandil on cold allodynia. In formalin test, nicorandil reduced flinches; an effect that was partially reversed by L-arginine and sildenafil but not by L-NAME, methylene blue or glibenclamide. Nicorandil reduced serum levels of the oxidative marker (MDA) and the inflammatory mediators (TNF-\u03b1, IL-6 and COX-2). Immunohistochemical studies revealed that nicorandil blunted the elevation of MAPK\n                    <jats:sub>ERK1\/2<\/jats:sub>\n                    protein expressions in DRG whereas naloxone reversed that suppression. L-arginine and sildenafil reversed nicorandil mediated improvements of histopathological milieu of sciatic nerves and DRG. Taken together, these data demonstrate that nicorandil has an antiallodynic effect on neuropathic and inflammatory pain via inhibition of NO\/cGMP pathways and reduction of oxidative stress and proinflammatory cytokines targeting ROS\/TNF-\u03b1, IL6 \/MAPK\n                    <jats:sub>ERK1\/2<\/jats:sub>\n                    signaling pathways. These findings highlight nicorandil\u2019s potential as a promising multitarget therapeutic option for pain management through its anti-inflammatory and antioxidant properties.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-35272-4","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T08:36:25Z","timestamp":1770021385000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nicorandil ameliorates neuropathic and inflammatory pain via TNF-\u03b1, IL6\/MAPKERK1\/2 and NO\/cGMP signaling"],"prefix":"10.1038","volume":"16","author":[{"given":"Rasha M.","family":"Badr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salwa A.","family":"Abuiessa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar S.","family":"Elblehi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham A.","family":"Afify","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"35272_CR1","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1007\/s00415-017-8641-6","volume":"265","author":"E St John Smith","year":"2018","unstructured":"St John Smith, E. 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