Deciphering the antinociceptive and anti-inflammatory effects of pelargonidin through L-arginine/nitric oxide/cyclic GMP/ATP-sensitive potassium channel signaling pathway and gamma-aminobutyric acid/opioidergic receptors.

Abstract

There are complex dysregulated pathways behind the pathogenesis of pain and inflammation. Because most of the present drugs have certain side effects or are not effective enough, providing novel multitargeting and potent therapeutic agents is of particular importance. This study investigates the antinociceptive effects of pelargonidin, an anthocyanin derived from various plants, through the modulation of the L-arginine/nitric oxide (NO)/cyclic GMP (cGMP)/ATP-sensitive potassium channel (KATP) signaling pathway. We also evaluated the anti-inflammatory role of pelargonidin passing through gamma-aminobutyric acid (GABA) and opioidergic receptors. Two experimental models were utilized. In the carrageenan model, 42 rats were divided into control, diclofenac, and three doses of pelargonidin (3, 6, and 9 mg/kg). In addition, two groups received pelargonidin 9 mg/kg + naloxone and pelargonidin 9 mg/kg + flumazenil. For the formalin model, 90 male mice were assigned to control, diclofenac, and three doses of pelargonidin, and 10 groups receiving L-arginine, S-nitroso-N-acetylpenicillamine (SNAP), N(gamma)-nitro-L-arginine methyl ester (L-NAME), glibenclamide, and sildenafil individually or alongside pelargonidin 9 mg/kg. Our results indicated that pelargonidin significantly decreased inflammation and pain in a dose-dependent manner. Notably, groups of pelargonidin 9 mg/kg + naloxone and pelargonidin 9 mg/kg + flumazenil diminished pelargonidin's anti-inflammatory effectiveness, underscoring the significant role of these receptors. Mechanistically, it was shown that the antinociceptive effects of pelargonidin were mediated by the NO signaling pathway. While L-NAME and glibenclamide reduced pelargonidin's antinociceptive efficacy, supplementation with sildenafil and SNAP enhanced the effect. This investigation demonstrated that pelargonidin possesses dose-dependent antinociceptive and anti-inflammatory actions through L-arginine/NO/cGMP/KATP pathways, and opioidergic and GABA receptors, respectively.