Differential modulation of endogenous cannabinoid CB1 and CB2 receptors in spontaneous and splice variants of ghrelin-induced food intake in conscious rats

Objective: Dysregulation of the endocannabinoid system can lead to the development of obesity and metabolic disorders. Endogenous endocannabinoids act on two cannabinoid receptor subtypes, type 1 (CB1) and type 2 (CB2), to exert their biological actions. The aim of this study was to determine whether CB1 and CB2 receptors modulate feeding behavior. Methods: We investigated the different roles of CB1 and CB2 receptors in spontaneous and centrally administered splice variants of ghrelin, O-n-octanoylated ghrelin and des-Gln¹⁴-ghrelin, stimulation of food intake in conscious rats. Results: Intraperitoneal (IP) injection of different doses of selective CB2 receptor antagonist AM-630 (0.3, 1, and 3mg/kg) enhanced cumulative food intake during the first 12h with a dome-shaped dose-response relationship in freely fed rats, with the most effective dose being 1mg/kg. In comparison, the selective CB1 receptor antagonist AM-251 (0.3, 1, and 3mg/kg, IP) dose-dependently suppressed the cumulative food intake in 16-h food-deprived rats. Centrally administered O-n-octanoylated ghrelin and des-Gln¹⁴-ghrelin-induced hyperphagic effects were counteracted dose-dependently by IP AM-251, but not AM-630. Conclusions: We demonstrated that the endogenous CB2 receptor plays a role in inhibiting food intake in the satiated state, whereas the CB1 receptor promotes food intake in the fasted condition. The induction of feeding by central acyl ghrelin is a CB1 receptor-dependent mechanism. Differentially nibbling CB1 and CB2 receptor subtypes may provide a new avenue to treating eating and metabolic disorders.