Mu- and delta-opioid receptor-mediated inhibition of adenylate cyclase activity stimulated by released endogenous dopamine in rat neostriatal slices; demonstration of potent delta-agonist activity of bremazocine

M. H. Heijna, F. Hogenboom, P. S. Portoghese, A. H. Mulder, A. N M Schoffelmeer

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Abstract

Rat neostriatal slices were superfused with medium containing 0.1 to 30 μM of the dopamine (DA)-releasing agent D-(+)-amphetamine (AMPH) and the D-2 DA receptor antagonist (-)-sulpiride (10 μM) in the absence or presence of mu-, delta-, and kappa-selective opioids. AMPH dose-dependently enhanced the cyclic AMP production, as measured by its efflux from striatal slices, whereas simultaneous blockade of D-2 DA receptors by (-)-sulpiride strongly potentiated this effect. Both the mu-opioid receptor selective agonist [D-Ala2,MePhe4,Gly-ol5]enkephalin (0.01-3 μM) and the delta-opioid receptor selective agonist [D-Phe2-D-Pen5]enkephalin (DPDPE, 0.01-3 μM) inhibited the cyclic AMP efflux, stimulated by 10 μM AMPH in the presence of (-)-sulpiride, by 70 to 80%. The highly selective kappa-opioid receptor agonist U 50,488 {trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzen acetamide methanesulfonate hydrate} (0.01-1 μM) had no effect. In contrast, the purposed kappa-opioid receptor agonist bremazocine (3-300 nM) inhibited the stimulated adenylate cyclase activity to a similar extent as did [D-Ala2-MePhe4,Gly-ol5]enkephalin and DPDPE. Moroever, the selective irreversible delta-antagonist fentanyl isothiocyanate reversed both the inhibition caused by DPDPE and that caused by bremazocine, whereas the kappa-selective antagonist norbinaltorphimine showed no differences in its potency to antagonize the inhibitory effects of the different opioid agonists. The results indicate that opioids, by activating mu- or delta-, but not kappa-opioid receptors may cause a profound inhibition of adenylate cyclase activity stimulated by activation of (postsynaptic) D-1 DA receptors upon the (presynaptic) release of DA. Furthermore, the purportedly selective kappa-opioid agonist bremazocine appears to display potent agonist activity at the delta-opioid receptors coupled to DA-sensitive adenylate cyclase, whereas previous studies have shown that it does not activate the delta-receptors mediating inhibition of striatal acetylcholine release.

Original languageEnglish (US)
Pages (from-to)864-868
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume249
Issue number3
StatePublished - Jan 1 1989

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