Evidence for the involvement of opioid and cannabinoid systems in the peripheral antinociception mediated by resveratrol

Despite all the development of modern medicine, around 100 compounds derived from natural products were undergoing clinical trials only at the end of 2013. Among these natural substances in clinical trials, we found the resveratrol (RES), a pharmacological multi-target drug. RES analgesic properties have been demonstrated, although the bases of these mechanisms have not been fully elucidated. The aim of this study was to evaluate the involvement of opioid and cannabinoid systems in RES-induced peripheral antinociception. Paw withdrawal method was used and hyperalgesia was induced by carrageenan (200 μg/paw). All drugs were given by intraplantar injection in male Swiss mice (n = 5). RES (100 μg/paw) administered in the right hind paw induced local antinociception that was antagonized by naloxone, non-selective opioid receptor antagonist, and clocinnamox, μOR selective antagonist. Naltrindole and nor-binaltorfimine, selective antagonists for δOR and kOR, respectively, did not reverse RES-induced peripheral antinociception. CB1R antagonist AM251, but not CB2R antagonist AM630, antagonized RES-induced peripheral antinociception. Peripheral antinociception of RES intermediate-dose (50 μg/paw) was increased by: (i) bestatin, inhibitor of endogenous opioid degradation involved-enzymes; (ii) MAFP, inhibitor of anandamide amidase; (iii) JZL184, inhibitor of 2-arachidonoylglycerol degradation involved-enzyme; (iv) VDM11, endocannabinoid reuptake inhibitor. Acute and peripheral administration of RES failed to affect the amount of μOR, CB1R and CB2R. Experimental data suggest that RES induces peripheral antinociception through μOR and CB1R activation by endogenous opioid and endocannabinoid releasing.