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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Drug Abuse Biomedical Research Review Committee (DABR)
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University of Missouri Kansas City
Schools of Medicine
Kansas City
United States
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Agbas, A; Ahmed, M S; Millington, W et al. (1995) Dynorphin A(1-8) in human placenta: amino acid sequence determined by tandem mass spectrometry. Peptides 16:623-7
Ahmed, M S; Cemerikic, B; Mou, S et al. (1993) Effects of methadone use during pregnancy on human placental opioid receptors. Membr Biochem 10:91-8
Cemerikic, B; Cheng, J; Agbas, A et al. (1991) Opioids regulate the release of human chorionic gonadotropin hormone from trophoblast tissue. Life Sci 49:813-24
Ahmed, M S; Zhou, D; Schoof, T et al. (1990) Illicit drug use during pregnancy: effects of opiates and cocaine on human placenta. NIDA Res Monogr 105:278-9
Ahmed, M S; Schoof, T; Zhou, D H et al. (1989) Kappa opioid receptors of human placental villi modulate acetylcholine release. Life Sci 45:2383-93