Agonist-induced opioid receptor phosphorylation is believed to be an important receptor regulatory process that promotes acute receptor desensitization, triggers internalization and recycling of the receptors, and participates the development of tolerance. Numerous lines of experimental evidence from studies of cell lines that express cloned opioid receptor indicate that in general the extent of MOR phosphorylation is dependent on the ligand efficacy, but also could be influenced differentially by ligands with similar efficacy (morphine vs methadone, for example) and specific signaling molecules in the different cells (CHO vs HEK). This implies that MOR phosphorylation could have differential roles in different brain regions. However, this has not been demonstrated in neuronal systems and whole animals. Therefore, the proposed research is aimed at testing the following hypothesis: MOR phosphorylation is agonist-dependent as well as region or cell specific, and the receptor's microenvironment and cellular signaling components influence the extent of phosphorylation and the development of differential tolerance and dependence in vivo. Using primary culture of DRG neurons as a model, the PI proposes to examine the MOR phosphorylation in DRG neuron and other brain regions; to evaluate its contribution to desensitizationin and other receptor regulatory processes by using phosphorylation-deficient mutant receptors; and to determine if cellular specific mu phosphorylation is a result of participation of different signaling components (such as different protein kinases) among the DRG and other brain regions. The PI also proposes to determine the effects of receptor dimerization on MOR phosphorylation, exploring the possible contributions of receptor dimerization to the potential regional variation in receptor phosphorylation and the development of opioid tolerence. The PI further proposes to test the hypothesis in vivo by modifying the MOR phosphorylation status in animal through generating MOR phosphorylation-deficient mutant mice using a knock-in approach. Thus, the results could lead to a better understanding the dynamic interplay between MOR phosphorylation and other receptor regulatory processes in neurons, and to provide potential explanations on the mechanism of differential development of tolerance and dependence among opioid drugs and new foundations for more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011925-09
Application #
7232640
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Lin, Geraline
Project Start
1998-09-30
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
9
Fiscal Year
2007
Total Cost
$281,609
Indirect Cost
Name
University of Maryland Baltimore
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201