Polydatin Relieves Nociceptive Pain: Possible Role of L-arginine/NO/cGMP/K<sub>ATP</sub> Channel Signaling Pathway in Mice

Background: The role of the L-arginine (L-Arg)/nitric oxide (NO)/cyclic GMP (cGMP)/ATP-sensitive potassium channel (KATP) channel pathway in pain regulation is well-known. Previous studies have confirmed the pain-relieving effects of polydatin, but the exact mechanisms behind anti-nociception are not fully understood. Objectives: This study aimed to investigate how the L-Arg/NO/cGMP/KATP channel pathway mediates the pain-relieving effects of polydatin in mice. Methods: The formalin test was employed to assess nociceptive pain. Mice were administered several compounds before receiving intraperitoneal doses of polydatin. The compounds included L-Arg, a precursor of NO; N(gamma)-nitro-l-arginine methyl ester (L-NAME), an inhibitor of NO synthase; and S-nitroso-N-acetylpenicillamine (SNAP), a donor of NO. Additionally, glibenclamide, a blocker of the KATP channel, and sildenafil, a phosphodiesterase inhibitor, were also administered. Results: The results showed that intraperitoneal injection of polydatin at different doses (5, 10, and 15 mg/kg) led to dose-dependent and significant anti-nociception in both the early and late phases of the formalin test. The anti-nociceptive effects of polydatin were augmented when mice were pretreated with SNAP, while pretreatment with L-NAME and glibenclamide reduced these effects in the formalin test. Conclusions: In conclusion, this study demonstrates the anti-nociceptive effect of polydatin and the involvement of the NO/cGMP/KATP channel pathway in such an effect.