Opiate drugs with abuse liability disrupt the genesis of neurons, astrocytes, and oligodendrocytes in the developing brain through their principal action on mu opioid receptors. In excess-opiates profoundly reduce the number of neurons and astrocytes in the brain. Despite the established importance of opioids in growth, the mechanisms by which mu opiate drugs with abuse liability intrinsically affect cell production are not completely understood. This grant focuses on the developmental neurobiology of opiate drugs of abuse and the intrinsic role of the mu opioid receptor in neuronal and glial maturation. Our goal is (1) to identify the populations of developing neural cells that intrinsically respond to mu opiate drugs, and (2) to determine the developmental consequences of opiate action per se on cell proliferation and survival. Our hypothesis is mu opioid receptors nominally regulate development and opiate drugs adversely affect CNS development by disrupting the maturation of mu receptor-expressing neuronal and glial populations. We predict that mu opiates affect CNS organization by reducing numbers of neurons, astrocytes, and by increasing oligodendrocyte numbers-thereby disrupting the numerical balance of cell types in the brain. To address this hypothesis, cellular and molecular development will be assessed in morphine-treated wild type and mu-opioid receptor knockout mice. Cell number as determined by cell proliferation and death.
Aim 1 will examine the intrinsic effect of mu opioid receptor activation on the proliferation and survival of neuroblasts, astroglia, and oligodendroglia in vitro.
Aim 2 consists of parallel studies that will explore mu receptor expression, as well as the developmental effects of mu-opioid receptor activation, in neurons, astrocytes, and oligodendrocytes in vivo. This research will systematically and unambiguously assess the effect of opiate drugs and the intrinsic role of the mu opioid receptor on neurogenesis and gliogenesis. The timing of our studies in mice mimics pre- and perinatal development in the humans. Our long-term goal is to understand the basic mechanisms by which the opioid system regulates CNS maturation.
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