Current treatments for human opioid abuse incorporate a variety of chronic pharmacotherapies, including methadone maintenance and newer therapies incorporating low efficacy opioid agonists (e.g., buprenorphine) or opioid antagonists (e.g., naltrexone). Preclinical studies of behavioral sequelae of such maintenance therapies may be useful in predicting behavioral and subjective effects of repeated opioid use in humans. The proposed projects will use drug discrimination assays and other behavioral assays as model systems to assess how pharmacological and behavioral factors modulate the development and expression of opioid tolerance and dependence during repeated treatment with clinically important opioid agonists. A primary goal during the upcoming period is to evaluate the hypothesis that abstinence precipitated by classical opioid antagonists in dependent organisms arises from inverse agonist actions, rather than from competitive antagonism, per se We will pay particular attention to the possibility that behavioral abstinence responses, as measured in free-operant, drug discrimination, and place conditioning assays, may represent uniquely sensitive indices of inverse agonist effects. Building on studies conducted during the previous award period, other experiments will evaluate whether the magnitude of dependence varies with the intrinsic efficacy of the agonist used to establish physical dependence Project 1 will define the doses, routes of administration, and pretreatment times over which compounds will function as antagonists of acute agonist actions of the classic ? agonists morphine and DAMGO. As controls for potential non-?, or non-opioid, mechanisms in morphine dependence, key antagonists will be compared for their ability to alter effects of ? and ? opioid agonists and selected non-opioids. Project 2 will assess the ability of classical and putative neutral opioid antagonists to provoke abstinence in acutely and chronically dependent organisms, focusing on performance altering and discriminative stimulus effects. Project 3 will assess the ability of compounds to produce a functional up regulation of opioid receptors. In order to begin an initial characterization of the potential aversive actions of classical and putative neutral opioid antagonists, Project 4 will assess the ability of promising compounds to establish place aversions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA003796-21
Application #
6969897
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Schnur, Paul
Project Start
1997-02-01
Project End
2007-06-30
Budget Start
2004-09-01
Budget End
2005-06-30
Support Year
21
Fiscal Year
2004
Total Cost
$370,265
Indirect Cost
Name
Texas Tech University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Chen, Yukun; Evola, Marianne; Young, Alice M (2013) Memantine and dizocilpine interactions with antinociceptive or discriminative stimulus effects of morphine in rats after acute or chronic treatment with morphine. Psychopharmacology (Berl) 225:187-99
Steinmiller, Caren L; Young, Alice M (2008) Pharmacological selectivity of CTAP in a warm water tail-withdrawal antinociception assay in rats. Psychopharmacology (Berl) 195:497-507
Walker, Ellen A; Young, Alice M (2002) Clocinnamox distinguishes opioid agonists according to relative efficacy in normal and morphine-treated rats trained to discriminate morphine. J Pharmacol Exp Ther 302:101-10
Young, A M (2001) Access conditions are crucial: comment on Lynch and Carroll (2001). Exp Clin Psychopharmacol 9:157-9; discussion 160-2
Walker, E A; Young, A M (2001) Differential tolerance to antinociceptive effects of mu opioids during repeated treatment with etonitazene, morphine, or buprenorphine in rats. Psychopharmacology (Berl) 154:131-42
Zhang, L; Walker, E A; Sutherland 2nd, J et al. (2000) Discriminative stimulus effects of two doses of fentanyl in rats: pharmacological selectivity and effect of training dose on agonist and antagonist effects of mu opioids. Psychopharmacology (Berl) 148:136-45
Walker, E A; Zernig, G; Young, A M (1998) In vivo apparent affinity and efficacy estimates for mu opiates in a rat tail-withdrawal assay. Psychopharmacology (Berl) 136:15-23
Makhay, M M; Young, A M; Poling, A (1998) Establishing morphine and U-50,488H as discriminative stimuli in a three-choice assay with pigeons. Exp Clin Psychopharmacol 6:3-9
Walker, E A; Richardson, T M; Young, A M (1997) Tolerance and cross-tolerance to morphine-like stimulus effects of mu opioids in rats. Psychopharmacology (Berl) 133:17-28
Young, A M; McMullen, W J; Makhay, M M et al. (1996) Behavioral contingencies modulate tolerance to discriminative stimulus effects of morphine. Psychopharmacology (Berl) 125:220-30

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