Our laboratory has made the initial observations suggesting that endogenous opioid peptides are related to nervous system development, and that perturbations of endogenous opioid/opioid receptor interactions markedly influence the course of neuroontogeny (Science 221:1179-1180, 1983). During the first 2 years of this project, the role of endogenous opioid systems in brain development has been carefully defined. We found that endogenous opioids modulate neurobiological maturation, and influence both cell proliferation, and differentiation. A major discovery was that endogenous opioid systems are involved in human brain development. Our hypothesis is that endogenous opioids serve to control brain development through interaction with opioid receptors associated with developing neural cells; this may reflect an autocrine mechanism of growth. In this grant proposal, we continue to explore this thesis using the developing rat cerebella, as a model.
The aims of this proposal are: (1) Identify the prototypic opioids related to growth through drug displacement studies and structure-function experiments. The binding site related to growth will be fully characterized, including assessment of kinetics, saturation, and interactions. (2) determine the location and distribution of growth-related opioids by immunoelectron microscopy. (3) Investigate whether developing neural tissues synthesize opioid precursors using in situ hybridization. (4) Isolate and identify the opioid receptor related to neural growth, and characterize the receptor in terms of size, subunit composition, peptide maps, and binding function as studied by reconstitution experiments. Our research efforts will contribute to comprehending normal brain development, and will have impact on understanding the etiology or neurodevelopmental-based dysfunction. Information derived from these studies may be used in designing strategies for intervention in some developmental disorders of the nervous system. This research is part of a long- range program in cellular and molecular neurobiology which seeks to understand 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 #
2R01NS020500-04
Application #
3400854
Study Section
Neurology A Study Section (NEUA)
Project Start
1984-09-01
Project End
1992-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
4
Fiscal Year
1988
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
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
Zagon, I S; Hytrek, S D; Smith, J P et al. (1997) Opioid growth factor (OGF) inhibits human pancreatic cancer transplanted into nude mice. Cancer Lett 112:167-75
Zagon, I S; Hurst, W J; McLaughlin, P J (1997) Transplacental transfer of naltrexone in rats. Life Sci 61:1261-7
McLaughlin, P J; Tobias, S W; Lang, C M et al. (1997) Chronic exposure to the opioid antagonist naltrexone during pregnancy: maternal and offspring effects. Physiol Behav 62:501-8

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