It has been estimated that maternal drug abuse and its treatment is placing epidemic-proportions of offspring at considerable risk each year in the United States alone. Exposure of pregnant humans and laboratory animals to opiates can result in a range of problems for their fetuses including developmental retardation. Since the etiology of many of the developmental abnormalities is unknown, it is important that we understand the types and functions of opioid systems in normal developing mammalian brain. Use of this knowledge to elucidate the mechanism by which opiate drugs influence opioid receptor mediated actions during early brain development may allow us to determine, prevent or reverse pathological effects of these drugs. The objectives of this proposal are to continue the characterization of opioid receptors in rodent brain focusing on the 55 kDa molecular weight mu and the kappa opioid binding sites that we have detected in the perinatal period. By affinity labeling with [125I]-beta-endorphin the glycoprotein nature and subcellular compartmentation of the 55 kDa mu site will be examined to determined whether it is an incompletely processed precursor or a transiently expressed functional receptor. Using homologous and heterologous competition binding assays followed by a computer analysis, the subtype specificity of mouse perinatal mu and kappa sites will be probed. The sequence of appearance of opioid receptor subtypes will be correlated with that of the endogenous opioid peptides, G protein subunits and the neurotrophic functions described below that are prevalent at this stage of development. The role of individual receptor subtypes and their mechanism of action in opioid receptor mediated inhibition of brain DNA synthesis and ornithine decarboxylase activity will be investigated in cultured rat fetal brain cell aggregates and in vivo. Mixed agonist-antagonists such as buprenorphine will be administered to pregnant rats or cultured rat fetal brain cell aggregates and the consequences to normal expression of opioid receptors and of their neurotrophic effects assessed. Since buprenorphine has recently been demonstrated to be a good candidate for pharmacotherapy in cocaine and /or heroin abuse, these results may be of significance to the treatment of maternal drug abuse.
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