ANTIPROGESTINS INHIBIT THE BINDING OF OPIOIDS TO MU-OPIOID RECEPTORS IN NERVOUS MEMBRANE PREPARATIONS

The present study showed that the glucocorticoid/progesterone antagoni sts, 17 beta-hydroxy-11 ino-phenyl-1)-17-(prop-1-ynyl)estra-4,9-dien-3 -one (RU486) and 17 beta-hydroxy-11 ino-phenyl-1)-17-(propan-3-ol)estr a-4,9-dien-3-one (ZK 98299), inhibit the binding of labeled dihydromor phine to mu-opioid receptors present on membrane preparations derived from rat and mouse brain, as well as from human neuroblastoma cells. T he inhibitory effect of RU486 was dose-dependent and linked to a decre ase of the affinity of labeled dihydromorphine to the mu-opioid recept ors. Kinetic experiments have shown that RU486 induces a decrease of t he association rate constant (k(+1)) of dihydromorphine. RU486 also pr oved able to dissociate the dihydromorphine-mu-opioid receptor complex , although at a rate slower than that exhibited by unlabeled dihydromo rphine. Finally, the addition of NaCl (100 mM) to the incubation buffe r induced a 50% decrease of the inhibitory effect of RU486. A 6-day tr eatment of neuroblastoma cells with RU486 eliminated the inhibitory ef fect morphine exerts on the intracellular accumulation of cyclic AMP i nduced by prostaglandin E(1). These results indicate that RU-486 may i nteract with brain mu-opioid receptors in vitro, by decreasing the aff inity of opioid ligands.