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 chronic methadone administration on binding and functional properties of placental kappa receptors. Viability parameters demonstrated that functional integrity of the tissue and its responsiveness to the modulation of human chorionic gonadotropin release by opioids are fully preserved during the 3 days of culture. Methadone administration for 2 days did 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 stimulation 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 binding properties that preceded the shift in responsiveness. These data suggest that the development of tolerance to opioids in human placenta starts with an apparent down regulation and change in the affinity of the receptors and may involve downstream events that transduce receptor activation into a biological response.