Antiprogestins inhibit the binding of opioids to μ-opioid receptors in nervous membrane preparations

• Published in: European journal of pharmacology 1996-04, Vol.301 (1), p.169-177
• Main Authors: Maggi, Roberto, Pimpinelli, Federica, Casulari, Luiz A., Piva, Flavio, Martini, Luciano
• Format: Article
• Language: English
• Subjects: Analgesics - pharmacology; Animals; Biological and medical sciences; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Dihydromorphine - pharmacokinetics; Diprenorphine - pharmacokinetics; Enkephalin, Ala-MePhe-Gly; Enkephalins - pharmacokinetics; Female; Fundamental and applied biological sciences. Psychology; Gonanes - pharmacology; Hormone Antagonists - pharmacology; Humans; In Vitro Techniques; Male; Mammalia; Membranes - drug effects; Membranes - metabolism; Mice; Mifepristone - pharmacology; Narcotic Antagonists - pharmacokinetics; Narcotics - pharmacokinetics; Nerve Tissue - drug effects; Nerve Tissue - metabolism; Nervous system; Nervous System Neoplasms - metabolism; Neuroblastoma; Neuroblastoma - metabolism; Opioid receptor; Progestins - antagonists & inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - drug effects; Receptors, Opioid, mu - metabolism; Sodium - pharmacology; Steroid; Tumor Cells, Cultured; Vertebrates: nervous system and sense organs
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/0014-2999(96)00003-9

The present study showed that the glucocorticoid/progesterone antagonists, 17β-hydroxy-11 β-(4-dimethylamino-phenyl-1)-17-(propl-ynyl)estra-4,9-dien-3-one (RU486) and 17β-hydroxy-11 β-(4-dimethylamino-phenyl-1)-17-(propan-3-ol)estra-4,9-dien-3-one (ZK 98299), inhibit the binding of labeled dihydromorphine to μ-opioid receptors present on membrane preparations derived from rat and mouse brain, as well as from human neuroblastoma cells. The inhibitory effect of RU486 was dose-dependent and linked to a decrease of the affinity of labeled dihydromorphine to the μ-opioid receptors. Kinetic experiments have shown that RU486 induces a decrease of the association rate constant ( k +1) of dihydromorphine. RU486 also proved able to dissociate the dihydromorphine-μ-opioid receptor complex, although at a rate slower than that exhibited by unlabeled dihydromorphine. Finally, the addition of NaCl (100 mM) to the incubation buffer induced a 50% decrease of the inhibitory effect of RU486. A 6-day treatment of neuroblastoma cells with RU486 eliminated the inhibitory effect morphine exerts on the intracellular accumulation of cyclic AMP induced by prostaglandin E 1. These results indicate that RU-486 may interact with brain μ-opioid receptors in vitro, by decreasing the affinity of opioid ligands.