Our long term objectives are the understanding of the molecular mechanisms leading to opioid tolerance and addiction in human. We have chosen a human organ, the placenta, as a model system for our studies. This organ offers several advantages such as human origin, availability, containing components of the opiate system--namely kappa receptors and their natural ligand dynorphin 1-8--which are affected by maternal opiate abuse during pregnancy. In addition, the human placental lobule can be perfused in vitro for up to 24 hours on the maternal and fetal side allowing studies on the effects of tertogens on its physiology. This proposal addresses three specific aims: the first, to characterize the isolated and purified kappa opiate receptor and its natural ligand dynorphin 1-B from placental villus tissue. The second, to study the physiologic significance of the placental villus tissue. The second, to study the physiologic significance of the placental opiate system namely opioid modulation of acetylcholine and LCG release from villus tissue. The third, to study the effects of maternal opioid abuse during pregnancy on the levels of the placental opiate system components i.e. up or down regulation and physiologic function i.e. acetylcholine and LCG release. Two main approaches will be used to obtain the data on the effects of opiate abuse during pregnancy: the first, by conducting experiments on placenta obtained from mothers in methadone treatment programs during pregnancy. The second, from experiments using placenta obtained from normal patients and perfusing them in vitro in a dual lobule persusion system with opiates for 24 hours. The data obtained from the two approaches will provide evidence for the chronic effects of opiates on placental physiology. The conclusions drawn will help us understand the mechanisms of opiate addiction in human.
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