The research proposal component of the application will evaluate the effects of both exogenous and endogenous agmatine in opioid-mediated events. Agmatine has been detected in mammalian central nervous system and found to antagonize NMDA receptors and inhibit nitric oxide synthase (NOS). Exogenously administered agmatine has also been shown to inhibit NMDA receptor/NOS-dependent behavior including chronic pain, and opioid tolerance and self-administration. These previous studies have been largely limited in terms of route of administration, dose-response, or pharmacodynamic evaluation. To determine the therapeutic window in which agmatine is effective for prevention of opioidergic events, exogenous agmatine will be administered centrally and systemically at varying time points in a model of spinal opioid analgesic tolerance as well as a model of opioid self-administration. Definition of the pharmacodynamic profile of exogenous agmatine in opioid-related behavior will advance our understanding of the therapeutic utility and endogenous role of this molecule. Elucidation of the role of the endogenous agmatine in opioid analgesic tolerance and drug abuse may lead to the identification of new therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA021054-03
Application #
7407397
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Avila, Albert
Project Start
2006-04-17
Project End
2010-04-16
Budget Start
2008-04-17
Budget End
2009-04-16
Support Year
3
Fiscal Year
2008
Total Cost
$31,296
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Wade, Carrie L; Krumenacher, Perry; Kitto, Kelley F et al. (2013) Effect of chronic pain on fentanyl self-administration in mice. PLoS One 8:e79239
Wade, Carrie L; Eskridge, Lori L; Nguyen, H Oanh X et al. (2009) Immunoneutralization of agmatine sensitizes mice to micro-opioid receptor tolerance. J Pharmacol Exp Ther 331:539-46
Wade, Carrie L; Schuster, Daniel J; Domingo, Kristine M et al. (2008) Supraspinally-administered agmatine attenuates the development of oral fentanyl self-administration. Eur J Pharmacol 587:135-40