Role of l-arginine/nitric oxide/cyclic GMP/KATP channel signaling pathway and opioid receptors in the antinociceptive effect of rutin in mice

Abstract

The l-arginine (l-Arg)/nitric oxide/cyclic GMP/potassium channel (KATP) pathway and opioid receptors are known to play critical roles in pain perception and the antinociceptive effects of various compounds. While there is evidence suggesting that the analgesic effects of rutin may involve nitric oxide modulation, the direct link between rutin and the l-Arg/nitric oxide/cyclic GMP/KATP pathway in the context of pain modulation requires further investigation. The antinociceptive effect of rutin was studied in male NMRI mice using the formalin test. To investigate the role of the l-Arg/nitric oxide/cyclic GMP/KATP pathway and opioid receptors, the mice were pretreated intraperitoneally with different substances. These substances included l-Arg (a precursor of nitric oxide), S-nitroso-N-acetylpenicillamine (SNAP, a nitric oxide donor), N(gamma)-nitro-l-arginine methyl ester (L-NAME, an inhibitor of nitric oxide synthase), sildenafil (an inhibitor of phosphodiesterase enzyme), glibenclamide (a KATP channel blocker), and naloxone (an opioid receptor antagonist). All pretreatments were administered 20 min before the administration of the most effective dose of rutin. Based on our investigation, it was found that rutin exhibited a dose-dependent antinociceptive effect. The administration of SNAP enhanced the analgesic effects of rutin during both the initial and secondary phases. Moreover, L-NAME, naloxone, and glibenclamide reduced the analgesic effects of rutin in both the primary and secondary phases. In conclusion, rutin holds significant value as a flavonoid with analgesic properties, and its analgesic effect is directly mediated through the nitric oxide/cyclic GMP/KATP channel pathway.