Pre- and postnatal exposure to opioids can profoundly affect CNS development and function. Since the fastest growing population of opiate (heroin) abusers are young women of childbearing years, there is a public health interest in understanding how opioid signaling affects CNS development. Opioids given experimentally in vivo or to slice cultures during pre- or perinatal periods can alter survival and proliferation of neurons and astroglia, cause permanent changes in CNS structure and adversely affect learning and memory. Opiate exposure also reduces neurogenesis in adult hippocampus by 40 percent. Opioid effects are complex. Depending on the cell type or receptor (mu, delta or kappa) targeted, opioids can be toxic or protective and can have distinct effects on cell maturation. The survival of oligodendrocytes (OLs) and formation of myelin is critical for CNS function. Although opiate abuse can result in myelin pathology, essentially nothing is known about opioid effects on OLs either during neonatal or perinatal periods or in the adult. Our work has defined the existence of opioid signaling pathways in cultured OLs by showing that: (a) OLs express mu- and kappa-opioid receptors in a temporally specific pattern; (b) OLs have physiologic responses (survival, proliferation, myelin production) to selective manipulation of receptors; (c) OLs synthesize, process and probably secrete 2 classes of endogenous opioids (dynorphins, enkephalins). The central goals of this proposal are to determine the spatiotemporal expression patterns of opioid receptors and peptides within the developing and mature CNS, and to determine the role that opioids play in modulating the survival and function of OLs. Functional studies center on the role of dynorphin peptides since our findings show dynorphin mediates effects on the survival of OLs and neurons. A secondary goal is to determine whether manipulation of opioid signaling pathways can promote OL survival and myelination in clinical conditions with myelin pathology. Proposed studies use complementary in vivo and in vitro approaches employing mice deficient in opioid receptors and dynorphin to: (1) Identify spatiotemporal patterns of opioid receptor expression on OLs in the CNS; (2) Identify spatiotemporal patterns of dynorphin expression on OLs in the CNS and determine if dynorphin peptides are secreted; (3) Test the hypothesis that signaling through kappa-opioid receptors promotes OL survival and activates the PI3-kinase/Aktl pathway; (4) Test the hypothesis that some dynorphin peptides have glutamatergic effects on OLs. Techniques used include cell culture, immunostaining, in situ hybridization, immunoblot, confocal microscopy and adenoviral transfection.
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