Beta-arrestin2-knockout (Beta-arr2-KO) mice display enhanced morphine-induced biological effects such as analgesia, while other responses like constipation are attenuated when compared to their wild-type (WT) littermates. Further, physical dependence appears to be unaffected by the loss of Beta-arr2 with chronic morphine treatment. While Beta-arr2 ablation produces enhanced morphine-induced analgesic responses, other opiates including methadone and fentanyl do not. We are now asking whether opiate-induced constipation and physical dependence will vary with the opiate drug used. Therefore, the overall goal of the research plan is to test the hypothesis that ablation of Beta-arr2 may alter the development of opioid-induced constipation and physical dependence in an agonist dependent manner. Beta-arr2-KO mice and their WT littermates will be tested in physiological and behavioral paradigms that measure gastrointestinal function and physical dependence after treatment with different opiate agonists including methadone and fentanyl. In addition, in vivo findings will be correlated with ex vivo physiological and biochemical assessments of mu-OR expression and function in these animals. The overall goal of this proposal as a whole is to develop my independent research career by introducing multifaceted approaches to study drug abuse problems in vivo. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA021952-02
Application #
7290934
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2006-09-30
Project End
2008-09-29
Budget Start
2007-09-30
Budget End
2008-09-29
Support Year
2
Fiscal Year
2007
Total Cost
$33,270
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Nguyen, Peter T; Schmid, Cullen L; Raehal, Kirsten M et al. (2012) ?-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biol Psychiatry 71:714-24
Raehal, Kirsten M; Schmid, Cullen L; Groer, Chad E et al. (2011) Functional selectivity at the ?-opioid receptor: implications for understanding opioid analgesia and tolerance. Pharmacol Rev 63:1001-19
Raehal, Kirsten M; Bohn, Laura M (2011) The role of beta-arrestin2 in the severity of antinociceptive tolerance and physical dependence induced by different opioid pain therapeutics. Neuropharmacology 60:58-65
Raehal, Kirsten M; Schmid, Cullen L; Medvedev, Ivan O et al. (2009) Morphine-induced physiological and behavioral responses in mice lacking G protein-coupled receptor kinase 6. Drug Alcohol Depend 104:187-96
Gupta, Achla; Rozenfeld, Raphael; Gomes, Ivone et al. (2008) Post-activation-mediated changes in opioid receptors detected by N-terminal antibodies. J Biol Chem 283:10735-44