This proposal's objective is to gain a better understanding of the molecular mechanisms underlying the development of tolerance of opiates. The findings of this study may contribute to the design of therapeutic agents that will provide analgesia comparable to that of morphine without inducing tolerance. These experiments will examine changes that occur in the mu receptor-signaling pathway in cultured cells. Additionally, they will examine changes that occur in the cellular localization of RGS4 in response to chronic mu agonist stimulation.
The specific aims are designed to answer the following: 1. Are RGS4 and the mu opioid receptor co-localized in the rat brain. Does chronic agonist treatment causes RGS4 translocation from the nucleus to the cytosol? 2. How does chronic DAMGO treatment enhances the efficacy of RGS4 in blunting mu opioid receptor mediated inhibition of adenylyl cyclase activity? The experiments are designed to test the following hypothesis: Chronic activation of the mu receptor causes RGS4 to translocate from the nucleus to the cytosol. Also, chronic mu receptor activation causes RGS4 to associate with the receptor, bringing RGS4 in close proximity to the receptor-associated Gi-type G proteins, resulting in an increase in the GTPase of these G proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DA014747-01A1
Application #
6551470
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2002-06-01
Project End
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
1
Fiscal Year
2002
Total Cost
$21,690
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
City
Rockville
State
MD
Country
United States
Zip Code
20817