“We hypothesized that the cannabinoid (CB) system may mediate the brain orexin- or ghrelin-induced visceral antinociception. Intraperitoneal injection of either CB_1/2 agonist, WIN 55212 or O-Arachidonoyl ethanolamine increased the threshold volume of colonic distension-induced abdominal withdrawal reflex in rats, suggesting CB could induce visceral antinociception. Pretreatment with either the CB₁ or CB₂ antagonist potently blocked the centrally injected orexin-A-induced antinociceptive action against colonic distension while CB₂ but not CB₁ antagonist blocked the brain ghrelin-induced visceral antinociception. These results suggest that the cannabinoid signaling may be involved in the central orexin- or ghrelin-induced antinociceptive action in a different mechanistic manner.”