Endocrine Abstracts

The hypothalamus plays a key role in the control of appetite and energy balance. The endogenous cannabinoids are widely distributed throughout the brain, including the hypothalamus, together with specific cannabinoid-1 (CB-1) receptors. Endogenous and exogenous cannabinoids induce hyperphagia, whereas the selective CB-1 receptor antagonist, SR 141716 (rimonabant), inhibits feeding and CB-1 knockout animals are leaner and eat less after an overnight fast. Ghrelin, the recently identified brain-gut peptide secreted largely from the stomach, also has orexigenic effects. Its receptor GHS-R1a is expressed in the hypothalamus, especially in the arcuate, ventromedial and paraventricular nuclei. Leptin can inhibit endogenous cannabinoids in the hypothalamus and reduce the expression of the GHS-R.

We hypothesised that ghrelin and endocannabinoid system might interact with each other in the control of appetite. A cannula was inserted into the hypothalamus of rats and after a week for recovery animals were randomly allocated to the following 4 groups: vehicle-vehicle, vehicle-ghrelin, SR141716-ghrelin and SR141716-vehicle. We administered ghrelin (100pmol) into the paraventricular nucleus of the hypothalamus and observed a two-fold increase in food intake in the first hour. The orexigenic effect of ghrelin was reversed by a small, systemic dose of the cannabinoid CB1 receptor antagonist SR141716 (1mg/kg). This is a sub-threshold dose of SR141716, which under our experimental conditions had no discernible effect on feeding when administered alone. The results obtained in this study indicate that the endogenous cannabinoids are another target for direct or indirect (perhaps through the release of NPY or AgRP) ghrelin actions. This is the first demonstration of a functional relationship between ghrelin and endocannabinoid systems, and while it needs to be further investigated, the effect of ghrelin on food intake when injected into the hypothalamus seems to be mediated by stimulation of cannabinoid release.