Drugs that have limited intrinsic efficacy at the mu-opioid receptor (i.e., partial agonists) are a unique class of opioids in that they bave minimal potential for abuse and physical dependence, yet retain many of the therapeutic properties of morphine of other full mu agonists. During the last two decades, these drugs have gained clinical importance as analgesics, substitutes for heroin dependence, and most recently as a treatment for cocaine dependence. As a consequence of their growing acceptance in clinical practice there is considerable interest in tbeir behavioral effects following both acute and chronic exposure. From a theoretical perspective, these drugs can be used as tools to advance our understanding of the fundamental properties of drugs with limited efficacy at the receptor site. It is the aim of the current proposal to examine the behavioral and pharmacological properties of partial mu agonists using assays of drug discrimination and schedule-controlled responding. Specifically, the proposed investigations are aimed at characterizing: (1) the discriminative stimulus properties of partial mu agonists, (2) the agonist and antagonist effects (i.e, their intrinsic efficacy) of partial mu agonists in discrimination tasks with high and low efficacy requirements, (3) the discriminative stimulus properties produced during withdrawal following chronic exposure to a partial mu agonist, (4) the relative potencies of naltrexone and the alkylating agent B-funaltrexamine as antagonists of the discriminative stimulus and rate-decreasing effects of partial mu agonists, and (5) the development of tolerance and cross-tolerance to the effects of partial mu agonists

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29DA007327-01
Application #
3461292
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1991-07-01
Project End
1996-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
Schools of Arts and Sciences
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Picker, M J; Cook, C D (1997) Discriminative stimulus effects of opioids in pigeons trained to discriminate fentanyl, bremazocine and water: evidence of pharmacological selectivity. Behav Pharmacol 8:160-73
Hughes, C E; Dykstra, L A (1997) Antagonism of the response rate-decreasing effects of meperidine and morphine by beta-funaltrexamine and naltrexone in squirrel monkeys. Drug Alcohol Depend 45:197-206
Smith, M A; Pitts, R C; Picker, M J (1997) Tolerance and cross tolerance to the accuracy- and rate-decreasing effects of mu opioids in rats responding under a fixed-consecutive-number schedule. Drug Alcohol Depend 46:19-30
Negus, S S; Morgan, D; Cook, C D et al. (1996) Effects of the delta opioid against BW373U86 in pigeons trained to discriminate fentanyl, bremazocine and water in a three-choice drug discrimination procedure. Psychopharmacology (Berl) 126:199-205
Hughes, C E; Habash, T; Dykstra, L A et al. (1996) Discriminative-stimulus effects of morphine in combination with alpha- and beta-noradrenergic agonists and antagonists in rats. Pharmacol Biochem Behav 53:979-86
Picker, M J; Benyas, S; Horwitz, J A et al. (1996) Discriminative stimulus effects of butorphanol: influence of training dose on the substitution patterns produced by Mu, Kappa and Delta opioid agonists. J Pharmacol Exp Ther 279:1130-41
Morgan, D; Picker, M J (1995) Discriminative stimulus effects of the 5HT1A agonist 8-OH-DPAT: attenuation by mu but not by kappa opioids. Psychopharmacology (Berl) 122:336-45
Picker, M J (1994) Kappa agonist and antagonist properties of mixed action opioids in a pigeon drug discrimination procedure. J Pharmacol Exp Ther 268:1190-8
Picker, M J; Yarbrough, J; Hughes, C E et al. (1993) Agonist and antagonist effects of mixed action opioids in the pigeon drug discrimination procedure: influence of training dose, intrinsic efficacy and interanimal differences. J Pharmacol Exp Ther 266:756-67
Picker, M J; Craft, R M; Negus, S S et al. (1992) Intermediate efficacy mu opioids: examination of their morphine-like stimulus effects and response rate-decreasing effects in morphine-tolerant rats. J Pharmacol Exp Ther 263:668-81