Opioid receptor antagonists discriminate between presynaptic mu and delta receptors and the adenylate cyclase-coupled opioid receptor complex in the brain

The present study addressed the question as to whether or not interacting mu and delta opioid receptors, which may constitute an opioid receptor complex-inhibitory coupled to adenylate cyclase in rat neostriatum, display different antagonistic properties than the classical (noncomplexed) mu and delta receptors. In concentrations that antagonized the presynaptic inhibitory effect of [D-Ala²,MePhe⁴,Gly-ol⁵]enkephalin (DAMGO) on [³H]norepinephrine release from rat neocortical slices, the cyclic somatostatin-related mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn- Thr-Pen-Thr-NH₂ did not affect the inhibition of dopamine-sensitive adenylate cyclase caused by DAMGO in neostriatal slices. The delta opioid receptor antagonist naltrindole appeared to be about 200-fold more effective as an antagonist against inhibitory effect of [D-Ser²(O-tert- butyl),Leu⁵]enkephalyl-Thr⁶ on [¹⁴C]acetylcholine release from neostriatal slices than against the inhibitory effect of DAMGO on [³H]norepinephrine release from neocortical slices, in agreement with the involvement of presynaptic delta and mu receptors; respectively. However, regarding the inhibitory effect of DAMGO and [D-Ser²(O-tert- butyl),Leu⁵]enkephalyl-Thr⁶ on adenylate cyclase activity in neostriatal slices, naltrindole not only displayed a very low affinity but also only 10- fold delta-selectivity. In striking contrast to D-Phe-Cys-Tyr-D-TRP-ORN-THR- PEN-THR-NH₂ and naltrindole, naloxone did not discriminate between the neurotransmitter release- and adenylate cyclase-inhibitory effects of DAMGO and [D-Ser²(O-tert-butyl),Leu⁵]enkephalyl-Thr⁶. These data strongly suggest that interacting mu and delta receptors in rat neostriatum display pharmacological characteristics that are clearly different from (presynaptic) mu, delta and kappa receptors in the brain, and indicate that the putative opioid receptor complex may represent a pharmacologically unique type of opioid receptor.