Our laboratory has made the initial observations suggesting that endogenous opioid systems are related to nervous system development, and that perturbations of neuro-ontogeny (Science 221:1179-1180, 1983). During the past 8 years of this project the role of endogenous opioid systems in brain development has been carefully defined. We have identified [Met]-enkephalin, derived from preproenkephalin A (PPE), as the native peptide that serves as an opioid growth factor (OGF). OGF regulates the proliferation of both neuronal and glial precursors through inhibitory channels. The source of this peptide appears to be both autocrine (germinative cells) and paracrine (macronneurons). OGF interacts with the nuclear-associated zeta opioid receptor to regulate growth. The binding subunits have been identified and characterized, and polyclonal and monoclonal antibodies generated to these polypeptides. In this grant proposal, we continue to explore the thesis that an endogenous opioid system is important to neurrobiological development.
The aims of this proposal are: (1) Determine the embryogenesis of OGF and PPE gene expression in the rat brain by immunocytochemistry, Northern analysis and in situ hybridization. (2) Define the ontogeny of the zeta receptor quantitatively (immunodot assay) and qualitatively (Western blotting and peptide mapping). (3) Ascertain the location of the zeta receptor by immunocytochemistry, immunoelectron microscopy, and in vitro autoradiography. (4) Isolate, purify, and characterize the native zeta receptor, and assess binding function by reconstitution experiments. (5) Clone and sequence the cDNA for the zeta receptor. (6) Examine the OGF and zeta receptor in developing human brain using immunocytochemistry, in vitro autoradiography, Western and ligand blotting, Northern analysis, and in situ hybridization. This research will contribute to comprehending the processes shaping normal brain development, and should be useful in understanding the etiology of developmentally-based neurobiological dysfunction. This research is part of a long-range program in cellular and molecular neurobiology which seeks to define the fundamental principles underlying normal and abnormal brain development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS020500-09A1
Application #
3400856
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1984-09-01
Project End
1996-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
9
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Pennsylvania State University
Department
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Zagon, I S; Wu, Y; McLaughlin, P J (1999) Opioid growth factor and organ development in rat and human embryos. Brain Res 839:313-22
Zagon, I S; Verderame, M F; Allen, S S et al. (1999) Cloning, sequencing, expression and function of a cDNA encoding a receptor for the opioid growth factor, [Met(5)]enkephalin. Brain Res 849:147-54
Wilson, R P; McLaughlin, P J; Lang, C M et al. (1998) Temporal variation in cellular proliferation during recornification of mouse tail skin. Cell Prolif 31:191-201
Zagon, I S; Tobias, S W; Hytrek, S D et al. (1998) Opioid receptor blockade throughout prenatal life confers long-term insensitivity to morphine and alters mu opioid receptors. Pharmacol Biochem Behav 59:201-7
Zagon, I S; Hurst, W J; McLaughlin, P J (1998) Naltrexone is not detected in preweaning rats following transplacental exposure: implications for growth modulation. Life Sci 62:221-8
Levin, R J; Wu, Y; McLaughlin, P J et al. (1997) Expression of the opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor in head and neck squamous cell carcinoma. Laryngoscope 107:335-9
Zagon, I S; Hurst, W J; McLaughlin, P J (1997) Identification of [Met5]-enkephalin in developing, adult, and renewing tissues by reversed-phase high performance liquid chromatography and radioimmunoassay. Life Sci 61:363-70
Zagon, I S; Wu, Y; McLaughlin, P J (1997) Opioid growth factor is present in human and mouse gastrointestinal tract and inhibits DNA synthesis. Am J Physiol 272:R1094-104
Zagon, I S; Tobias, S W; McLaughlin, P J (1997) Endogenous opioids and prenatal determinants of neuroplasticity. Adv Exp Med Biol 429:289-303
McLaughlin, P J; Tobias, S W; Lang, C M et al. (1997) Opioid receptor blockade during prenatal life modifies postnatal behavioral development. Pharmacol Biochem Behav 58:1075-82

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