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

Abstract

ObjectiveDysregulation 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. MethodsWe 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. ResultsIntraperitoneal (IP) injection of different doses of selective CB2 receptor antagonist AM-630 (0.3, 1, and 3 mg/kg) enhanced cumulative food intake during the first 12 h with a dome-shaped dose-response relationship in freely fed rats, with the most effective dose being 1 mg/kg. In comparison, the selective CB1 receptor antagonist AM-251 (0.3, 1, and 3 mg/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. ConclusionsWe 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.