PT  - JOURNAL ARTICLE
AU  - Donna M. Platt
AU  - James K. Rowlett
AU  - Roger D. Spealman
TI  - Discriminative Stimulus Effects of Intravenous Heroin and Its Metabolites in Rhesus Monkeys: Opioid and Dopaminergic Mechanisms
DP  - 2001 Nov 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 760--767
VI  - 299
IP  - 2
4099  - http://jpet.aspetjournals.org/content/299/2/760.short
4100  - http://jpet.aspetjournals.org/content/299/2/760.full
SO  - J Pharmacol Exp Ther2001 Nov 01; 299
AB  - Heroin has characteristic subjective effects that contribute importantly to its widespread abuse. Drug discrimination procedures in animals have proven to be useful models for investigating pharmacological mechanisms underlying the subjective effects of drugs in humans. However, surprisingly little information exists concerning the mechanisms underlying the discriminative stimulus (DS) effects of heroin. This study characterized the DS effects of heroin in rhesus monkeys trained to discriminate i.v. heroin from saline. In drug substitution experiments, heroin, its metabolites 6-monoacetylmorphine, morphine, morphine-6-glucuronide, and morphine-3-glucuronide, and the μ-agonists fentanyl and methadone engendered dose-dependent increases in heroin-lever responding, reaching average maximums of >80% (full substitution) at doses that did not appreciably suppress response rate. In contrast, the δ-agonist SNC 80, the κ-agonist spiradoline, and the dopamine uptake blockers/releasers cocaine, methamphetamine, and GBR 12909 did not engender heroin-like DS effects regardless of dose. In antagonism studies, in vivo apparent pA2 and pKB values for naltrexone combined with heroin, morphine, and 6-monoacetylmorphine (8.0–8.7) were comparable with those reported previously for naltrexone antagonism of prototypical μ-agonists. The results show that the DS effects of heroin are pharmacologically specific and mediated primarily at μ-opioid receptors. Moreover, the acetylated and glucuronated metabolites of heroin appear to play significant roles in these effects. Despite previous speculation that morphine-3-glucuronide lacks significant opioid activity, it substituted fully for heroin in our study, suggesting that it can exhibit prominent μ-agonist effects in vivo. The American Society for Pharmacology and Experimental Therapeutics