The G-protein activations induced by kappa-opioid receptor agonists, (-)U50,488H, U69,593 and TRK-820 in the mouse lower midbrain, striatum and limbic forebrain were determined by monitoring guanosine-5'-o-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding. All kappa-opioid receptor agonists produced approximately 40, 20 and 10% increases of [35S]GTP gamma S binding over baseline in the lower midbrain, striatum and limbic forebrain, respectively. The increases of [35S]GTP gamma S binding induced by kappa-opioid receptor agonists were completely reversed by the selective kappa-opioid receptor antagonist, norbinaltorphimine (norBNI), in all brain regions. The intrinsic activities of kappa-opioid receptor agonists for G-protein activation in brain regions observed in the present study are not correlated with densities of kappa-opioid receptor binding sites from previous reports. The present results suggest that the catalytic efficiency of kappa-opioid receptor-G-protein coupling may be variable in different brain regions.