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.
Rat neostriatal slices were superfused with medium containing 0.1 to 30 microM of the dopamine (DA)-releasing agent D-(+)-am-phetamine (AMPH) and the D-2 DA receptor antagonist (-)-sulpiride (10 microM) 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 microM) and the delta-opioid receptor selective agonist [D-Phe2-D-Pen5]enkephalin (DPDPE, 0.01-3 microM) inhibited the cyclic AMP efflux, stimulated by 10 microM 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-pyrrol-idinyl)- cyclohexyl]benzeneacetamide methanesulfonate hydrate) (0.01-1 microM) had no effect. In contrast, the purported 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. Moreover, 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Heijna
M H
MH
Department of Pharmacology, Free University/Medical Faculty, Amsterdam, The Netherlands.
Hogenboom
F
F
Portoghese
P S
PS
Mulder
A H
AH
Schoffelmeer
A N
AN
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001575:Benzomorphans / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism / Q000502:physiology*; D004347:Drug Interactions; D008297:Male; D009019:Morphinans / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*
D001575:Benzomorphans; D009019:Morphinans; D009294:Narcotics; D011957:Receptors, Opioid; D000661:Amphetamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C027248:bremazocine; D004298:Dopamine