Maternal drug abuse places hundreds of thousands of progeny at risk each year in the US. The opiate problem has become exacerbated recently, due to the greater availability of purer heroin and an increase in young abusers. The effect of opioids on growth factor regulation of cell proliferation in the fetus of drug-addicted mothers may contribute to physiological and psychological delays observed in their offspring. Chronic mu opioids display antiproliferative effects in transformed cells, primary cultures and developing brain. Opioids also modulate proliferation of adult neuroprogenitor cells via the MAP kinase, ERK. The fact that neuroprogenitor cells have an astrocytic lineage and chronic heroin suppresses adult neurogenesis causing long-term disruptions in neuroplasticity, provides even more compelling reasons to study the fundamental mechanism by which heroin perturbs cellular maturation. The delineation of the mechanism of opioid-induced signaling that regulates ERK and ultimately cell proliferation has been a major theme of our research. Astroglia are a principal target of chronic mu opioid antiproliferative actions. Salient mechanistic features of opioid heterologous signaling in astrocytes were determined. Mu opioid agonists induced a short-lived activation of ERK, whereas a mu agonist elicited a sustained activation of ERK in astrocytes. Acute kappa and mu opioids induce the transactivation of the EGF receptor (EGFR) and chronic mu opioids cause its down regulation. Our hypothesis is: Chronic mu opioid agonists down regulate EGFR via phosphorylation of its Ser/Thr residues and diversion of its trafficking from early endosomes to lysosomes in astrocytes. In addition, we postulate that acute ? and ? opioid activate ERK via matrix metalloproteinase-mediated EGFR transactivation and the process is calmodulin (CaM)-dependent. There are three specific aims:
AIM 1 Characterize the mechanism of chronic mu opioid-induced desensitization and down regulation of EGFR and determine why kappa opioids do not down regulate EGFR.
AIM 2 Determine the CaM-dependency of opioid-mediated transactivation and down regulation of EGFR.
AIM 3 Identify the matrix metalloproteinase(s) involved in opioid-induced EGFR transactivation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005412-15
Application #
7068571
Study Section
Special Emphasis Panel (ZRG1-MDCN-A (05))
Program Officer
Wu, Da-Yu
Project Start
1987-09-30
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
15
Fiscal Year
2006
Total Cost
$322,978
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Belcheva, Mariana M; Haas, Paul D; Tan, Yun et al. (2002) The fibroblast growth factor receptor is at the site of convergence between mu-opioid receptor and growth factor signaling pathways in rat C6 glioma cells. J Pharmacol Exp Ther 303:909-18
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