Nicorandil ameliorates neuropathic and inflammatory pain via TNF-α, IL6/MAPK<sub>ERK1/2</sub> and NO/cGMP signaling.

Abstract

Recently, nicorandil exerted antinociception via TRPV1/opioid signaling. Herein, the entanglement of downstream signals and NO-cGMP-K_ATP 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 MAPK_ERK1/2 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-α, IL6 /MAPK_ERK1/2 signaling pathways. These findings highlight nicorandil's potential as a promising multitarget therapeutic option for pain management through its anti-inflammatory and antioxidant properties.