Evidências de envolvimento das vias opioidérgica, canabinoidérgica e nitrérgica nos mecanismos antinociceptivos central e periférico do resveratrol em camundongos

Abstract

INTRODUCTION: Resveratrol is a natural phytoalexin present in grapes and derivatives, with widely reported therapeutic activities, including analgesic effects. However, the mechanisms of the antinociceptive action of resveratrol have not yet been fully elucidated, and it may promote limitations in its therapeutic use. OBJECTIVE: This work proposes to evaluate the mechanisms of central and peripheral antinociceptive effect induced by resveratrol, analyzing the possible involvement of the opioid, cannabinoid and nitrergic systems. METHODS: The paw withdrawal test was used and hyperalgesia was induced by intraplantar injection of carrageenan (200 μg). Resveratrol and drugs from analgesic systems evaluated were administered intraplantarly or intracerebroventricularly in male mice (n = 5). Statistical analyzes: One-Way ANOVA followed by Bonferroni post-test. RESULTS: Our results confirm that resveratrol has central and peripheral antinociceptive activity, dose and time dependent. This antinociception is due to the concomitant activation of the μ- and δ-opioid receptors and the CB1-type cannabinoid receptors. The antihyperalgesic effect of resveratrol also seems to involve the release of endogenous opioids and endocannabinoids, since the administration of non-analgesic doses of inhibitors of the reuptake or degradation of endocannabinoids and opioid peptides has intensified the antinociceptive effect of low doses of resveratrol. In addition, the administration of resveratrol activated a neuronal isoform of nitric oxide synthase and increased the tissue levels of nitrite quantified by the Griess method. Additionally, the antinociception triggered by resveratrol seems to depend on the action of soluble guanylate cyclase (GCs) and cyclic guanosine monophosphate (cGMP) levels. CONCLUSION: Our results provide evidence that central and peripheral resveratrol-induced antinociception is associated with the concomitant activation of μ- and δ-opioid receptors, CB1-type cannabinoid receptors and the neuronal isoform of nitric oxide synthase, with the possible action of endogenous opioids, endocannabinoids and GCs/cGMPs as cellular messengers. FINANCIAL SUPPORT: CNPq, CAPES and FAPEMIG. CEUA Protocol: 278/2016.