Pharmacological profile of various κ‐agonists at κ‐, μ‐ and δ‐opioid receptors mediating presynaptic inhibition of neurotransmitter release in the rat brain

Open Access
Publisher Website
Google Scholar
Abstract
1 The potency, relative efficacy and selectivity of a series of κ-opioid receptor agonists at the μ-, δ- and κ-opioid receptors mediating inhibition of electrically-induced (radiolabelled) neurotransmitter release from superfused rat brain slices was determined. 2 With regard to their potencies at κ-receptors mediating inhibition of striatal [3H]-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 κ-agonists (maximum inhibition being 60–70%). In contrast to the other κ-agonists, at a concentration of 1 μm, PD117302 caused a significant (25–40%) increase of the spontaneous efflux of tritium. 3 None of the κ-agonists significantly affected striatal [14C]-acetylcholine (ACh) release, with the exception of a slight inhibitory effect of EKC. The δ-receptor-mediated inhibitory effect of [d-Ala2, d-Leu5] enkephalin (DADLE) on [14C]-ACh release was antagonized in a concentration-dependent manner by bremazocine (0.1 and 1.0 μm) and also partially by EKC (1 μm), but not by the other κ-agonists. The pA2 value for bremazocine as an antagonist at the δ-receptors involved was 8.0, compared to 7.6 for naloxone. 4 None of the κ-agonists significantly affected cortical [3H]-noradrenaline (NA) release, with the notable exception of tifluadom, which strongly inhibited release by activating μ-receptors. The μ-receptor-mediated inhibitory effect of Tyr-d-Ala-Gly-(NMe)Phe-Gly-ol (DAMGO) on [3H]-NA release was antagonized in a concentration-dependent manner by bremazocine and EKC, but not by the other κ-agonists. The pA2 value for bremazocine as an antagonist at the μ-receptors involved was 8.2, compared to 8.6 for naloxone. 5 Thus, whereas U69593 and PD117302 display high potency and selectivity towards κ-opioid receptors, the potent benzomorphan κ-agonists bremazocine and EKC also appear to be strong μ-opioid receptor antagonists.