Nicorandil ameliorates neuropathic and inflammatory pain via TNF-α, IL6/MAPKERK1/2 and NO/cGMP signaling
Abstract
Recently, nicorandil exerted antinociception via TRPV1/opioid signaling. Herein, the entanglement of downstream signals and NO-cGMP-KATP 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 mg/kg, twice, 2 h apart, PO) reversed mechanical and cold allodynia induced by CCI, reduced the licking time and number of flinches in formalin test. L-arginine (500 mg/kg, I.P), N(ω)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, I.P), methylene blue (10 mg/kg, I.P), sildenafil (2.5 mg/kg, I.P) and glibenclamide (5 mg/kg, I.P) were tested 30 min 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-α, IL-6 and COX-2). Immunohistochemical studies revealed that nicorandil blunted the elevation of MAPKERK1/2 protein expressions in DRG whereas naloxone reversed that suppression. L-arginine and sildenafil reversed nicorandil mediated improvements of histopathological milieu of…
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