Discriminative stimulus effects of intravenous heroin and its metabolites in rhesus monkeys: opioid and dopaminergic mechanisms.
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 mu-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 delta-agonist SNC 80, the kappa-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 pK(B) 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 mu-agonists. The results show that the DS effects of heroin are pharmacologically specific and mediated primarily at mu-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 mu-agonist effects in vivo.
Platt
D M
DM
Harvard Medical School, New England Regional Primate Research Center, Southborough, Massachusetts 01772-9102, USA. donna_platt@hms.harvard.edu
Rowlett
J K
JK
Spealman
R D
RD
D000818:Animals; D004192:Discrimination, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005793:Generalization, Psychological; D003932:Heroin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D008297:Male; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011954:Receptors, Dopamine / Q000187:drug effects*; D011957:Receptors, Opioid / Q000187:drug effects*
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D009294:Narcotics; D011954:Receptors, Dopamine; D011957:Receptors, Opioid; D009271:Naltrexone; D003932:Heroin; D004298:Dopamine