Previous studies have revealed that cannabinoid (CB)-receptor agonists inhibit gastric acid secretion stimulated by indirectly acting agents, but not by histamine. Aiming to investigate whether central or peripheral mechanisms are involved, the effects of the synthetic CB-receptor agonists WIN55,212-2 and HU-210, administered either intracerebroventricularly (i.c.v.) or intravenously (i.v.) to the anaesthetized rat with lumen-perfused stomach, against gastric acid secretion induced by pentagastrin were tested. Injected i.c.v., both WIN55,212-2 (50 and 100 mug/kg) and HU-210 (25, 50 and 100 mug/kg) were ineffective on either basal secretion or acid output induced by pentagastrin (7.7 mug/kg, i.v.). By contrast, i.v. injections of WIN55,212-2 (100 and 1000 mug/kg) or HU-210 (10-100 mug/kg) significantly inhibited pentagastrin-induced acid secretion, maximal reductions being 75.70 and 82.24% for WIN55,212-2 and HU-210, respectively. The gastric antisecretory effect of HU-210 was prevented by administration of the selective CB1-receptor antagonist SR141716A (1000 mug/kg, i.v.). These results show that CB1-receptors mediating inhibition of gastric acid secretion in the rat are mainly peripherally located.