The role of neuropeptides in the complex developmental processes which underlie the morphogenesis of mammalian brain is currently unknown. Opioid peptides and their receptors appear early in ontogeny, being detectable within embryonic rat brain by the fourteenth day of gestation. Data from both clinical and animal studies suggest that opioid receptors may possess some functional capacity at an early stage of neurogenesis. Our goal is to use a combination of neuroanatomical and biochemical techniques to elucidate several aspects of the ontogeny, and possible developmental role, of opioid systems within the CNS. Autoradiographic techniques will be used to continue our detailed studies of the development of opioid receptors within rat brain. We shall undertake both quantitative and qualitative analyses of the developmental appearance of Beta-endorphin binding sites. In a parallel study, caudate putamen will be used as a model in which to compare the detailed temporal and spatial relationships between opioid peptide and receptor development. Further experiments, in intact animals, are designed to identify possible developmental roles of endogenous opioid systems in the control of cellular proliferation and migration. Both quantitative autoradiographic and biochemical techniques will be used to further characterize the effects of exogenous and endogenous opioids on DNA synthesis within neonatal rat brain. Combined (3H) thymidine autoradiographic and immunohistochemical techniques will be used to characterize the """"""""birthdate"""""""" of a recently identified population of Beta-endorphin immunoreactive cells which appear transiently within subventricular germinal zone. Immunohistochemical co-localization techniques will be used for a more detailed examination of the effects of opioids on the growth and survival of developing neural cells. Opioid actions will be examined, both in untreated cultures, and in those which have been stimulated by growth factors. The effects of growth factors on the development of opioid systems in culture will also be determined. These studies are important in that they may provide some insight as to the organizational principles which underlie neuronal development within mammalian CNS, as well as to possible consequences, to the offspring, of maternal drug abuse.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurological Sciences Subcommittee 1 (NLS)
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University of California Irvine
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Winzer-Serhan, Ursula H; Chen, Yiling; Leslie, Frances M (2003) Expression of opioid peptides and receptors in striatum and substantia nigra during rat brain development. J Chem Neuroanat 26:17-36
Leslie, F M; Chen, Y; Winzer-Serhan, U H (1998) Opioid receptor and peptide mRNA expression in proliferative zones of fetal rat central nervous system. Can J Physiol Pharmacol 76:284-93
Kitchen, I; Leslie, F M; Kelly, M et al. (1995) Development of delta-opioid receptor subtypes and the regulatory role of weaning: radioligand binding, autoradiography and in situ hybridization studies. J Pharmacol Exp Ther 275:1597-607
Raymon, H K; Leslie, F M (1994) Opioid effects on [3H]norepinephrine release from dissociated embryonic locus coeruleus cell cultures. J Neurochem 62:1015-24
Smith, J A; Leslie, F M; Broide, R S et al. (1993) Long-term changes in striatal opioid systems after 6-hydroxydopamine lesion of rat substantia nigra. Neuroscience 55:935-51
Raymon, H K; Smith, T D; Leslie, F M (1992) Further pharmacological characterization of [3H]idazoxan binding sites in rat brain: evidence for predominant labeling of alpha 2-adrenergic receptors. Brain Res 582:261-7
Smith, J A; Loughlin, S E; Leslie, F M (1992) kappa-Opioid inhibition of [3H]dopamine release from rat ventral mesencephalic dissociated cell cultures. Mol Pharmacol 42:575-83
Loughlin, S E; An, A; Leslie, F M (1992) Opioid receptor changes in weaver mouse striatum. Brain Res 585:149-55
Arnsten, A F; Leslie, F M (1991) Behavioral and receptor binding analysis of the alpha 2-adrenergic agonist, 5-bromo-6 [2-imidazoline-2-yl amino] quinoxaline (UK-14304): evidence for cognitive enhancement at an alpha 2-adrenoceptor subtype. Neuropharmacology 30:1279-89
Loughlin, S E; Kornblum, H I; Massamiri, T et al. (1991) Transient appearance of beta-endorphin immunoreactive cells within the germinal zone of neonatal rat forebrain. Int J Dev Neurosci 9:493-500

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