title: Antiprogestins inhibit the binding of opioids to mu-opioid receptors in nervous membrane preparations.
abstract: The present study showed that the glucocorticoid/progesterone antagonists, 17 beta-hydroxy-1 1 beta-(4-dimethylamino-phenyl-1)-17-(prop-1-ynyl)estra-4,9-dien+ ++-3-one (RU486) and 17 beta-hydroxy-11 beta-(4-dimethylamino-phenyl-1)-17-(propan-3-ol)estra-4,9-dien-3-o ne (ZK 98299), inhibit the binding of labeled dihydromorphine to mu-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 mu-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-mu-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 E1. These results indicate that RU-486 may interact with brain mu-opioid receptors in vitro, by decreasing the affinity of opioid ligands.
authors.affiliation: Department of Endocrinology, University of Milan, Italy maggir@isfunix.farma.unimi.it
authors.forename: R
authors.initials: R
authors.lastname: Maggi
authors.forename: F
authors.initials: F
authors.lastname: Pimpinelli
authors.forename: L A
authors.initials: LA
authors.lastname: Casulari
authors.forename: F
authors.initials: F
authors.lastname: Piva
authors.forename: L
authors.initials: L
authors.lastname: Martini
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D004090:Dihydromorphine / Q000493:pharmacokinetics; D004174:Diprenorphine / Q000493:pharmacokinetics; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000493:pharmacokinetics; D005260:Female; D006067:Gonanes / Q000494:pharmacology*; D006727:Hormone Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D015735:Mifepristone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000493:pharmacokinetics; D009294:Narcotics / Q000493:pharmacokinetics; D009417:Nerve Tissue / Q000187:drug effects / Q000378:metabolism*; D009423:Nervous System Neoplasms / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism; D011372:Progestins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D012964:Sodium / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000700:Analgesics; D004745:Enkephalins; D006067:Gonanes; D006727:Hormone Antagonists; D009292:Narcotic Antagonists; D009294:Narcotics; D011372:Progestins; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004174:Diprenorphine; D015735:Mifepristone; D012964:Sodium; D004090:Dihydromorphine; C053238:onapristone