PHARMACOLOGICAL PROFILE OF VARIOUS KAPPA-AGONISTS AT KAPPA-OPIOID, MU-OPIOID AND DELTA-OPIOID RECEPTORS MEDIATING PRESYNAPTIC INHIBITION OF NEUROTRANSMITTER RELEASE IN THE RAT-BRAIN

1 The potency, relative efficacy and selectivity of a series of kappa-opioid receptor agonists at the mu-, delta- and kappa-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2 With regard to their potencies at kappa-receptors mediating inhibition of striatal [H-3]-dopamine release, the highest pD2 value (8.7) was found for bremazocine and the lowest (7.1) for U50488; the pD2 values for ethylketocyclazocine (EKC), tifluadom, U69593 and PD117302 were between 8.0 and 8.3. There were no marked differences between the relative efficacies of the kappa-agonists (maximum inhibition being 60-70%). In contrast to the other kappa-agonists, at a concentration of 1-mu-M, PD117302 caused a significant (25-40%) increase of the spontaneous efflux of tritium. 3 None of the kappa-agonists significantly affected striatal [C-14]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The delta-receptor-mediated inhibitory effect of [D-Ala2, D-Leu5] enkephalin (DADLE) on [C-14]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0-mu-M) and also partially by EKC (1-mu-M), but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the delta-receptors involved was 8.0, compared to 7.6 for naloxone. 4 None of the kappa-agonists significantly affected cortical [H-3]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating mu-receptors. The mu-receptor-mediated inhibitory effect of Tyr-D-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [H-3]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other kappa-agonists. The pA2 value for bremazocine as an antagonist at the mu-receptors involved was 8.2, compared to 8.6 for naloxone. 5 Thus, whereas U69593 and PD117302 display high potency and selectivity towards kappa-opioid receptors, the potent benzomorphan kappa-agonists bremazocine and EKC also appear to be strong mu-opioid receptor antagonists.