OPIOID TOLERANCE IN HUMAN PLACENTA DUE TO IN-VITRO METHADONE ADMINISTRATION

Explant culture of term placental villus trophoblast was investigated for its possible use as a model system for study of the effects of chr onic methadone administration on binding and functional properties of placental kappa receptors. Viability parameters demonstrated that func tional integrity of the tissue and its responsiveness to the modulatio n of human chorionic gonadotropin release by opioids are fully preserv ed during the 3 days of culture. Methadone administration for 2 days d id not affect the viability of cultured explants. However, it resulted in the development of opioid tolerance, as demonstrated by a shift to the right in the concentration-response curve of U-69,593-induced sti mulation of human chorionic gonadotropin release, and irresponsiveness to the inhibitory action of the antagonist nor-binaltorphimine. Kappa receptors of methadone-treated explants exhibited changes in their bi nding properties that preceded the shift in responsiveness. These data suggest that the development of tolerance to opioids in human placent a starts with an apparent down regulation and change in the affinity o f the receptors and may involve downstream events that transduce recep tor activation into a biological response.