Prolonged agonist exposure causes desensitization of the mu, delta, and kappa opioid receptors by mechanisms that are still incompletely understood. Opioid receptor desensitization is likely to involve a reduction in the efficiency by which agonist-bound receptor catalyzes the activation of G proteins. Evidence suggests that prolonged agonist exposure results in opioid receptor phosphorylation by a G protein coupled receptor kinase followed by the binding of beta-arrestin, although desensitization mediated by other kinases has also been suggested. We p ropose to extend our studies of opioid receptor desensitization mechanisms by defining the effects of specific kinases on the coupling between opioid receptor activation and inwardly rectifying potassium channels heterologously expressed in Xenopus oocytes, by comparing the effects of specific receptor mutations on desensitization in AtT20, a mammalian cell line, and by defining the regulation of coupling between opioid receptors and potassium channels naturally expressed in hippocampal neurons. Using these three cellular systems as models for components in vivo tolerance processes, we will address the questions: which kinases are effective in mediating homologous desensitization, and which domains of the receptors are the critical targets of phosphorylation. Because desensitization is likely to be an important component of opioid tolerance, the identification of the key mediators of desensitization would be significant and would suggest potential targets of drug development that might be useful in controlling opioid tolerance. The resulting knowledge is expected to provide a more rational basis for treating the consequences of prolonged opioid exposure.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011672-05
Application #
6634241
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Koustova, Elena
Project Start
1999-05-01
Project End
2004-07-04
Budget Start
2003-03-01
Budget End
2004-07-04
Support Year
5
Fiscal Year
2003
Total Cost
$235,670
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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