Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms.
OBJECTIVE
Opioid agonists frequently have been reported to share discriminative stimulus (DS) effects with cocaine; however, the pharmacological basis of these shared effects is not understood completely. The present study assessed the ability of heroin and its deacetylated metabolites, 6-monoacetylmorphine (6-MAM) and morphine, to engender cocaine-like DS effects and investigated the role of opioid receptor subtypes in modulating these DS effects.


METHODS
Squirrel monkeys were trained to discriminate 0.3 mg/kg cocaine (i.m.) from vehicle under a 10-response fixed-ratio schedule of food reinforcement, and responding on the drug lever was assessed after varying i.m. doses of heroin, 6-MAM, and morphine. The potential role of opioid receptor mechanisms in modulating the cocaine-like DS effects of heroin and its metabolites was assessed with the mixed mu/kappa opioid antagonist naltrexone, the delta-selective antagonist naltrindole, and the kappa-selective antagonist nor-binaltorphimine.


RESULTS
Heroin, 6-MAM, and morphine engendered dose-related increases in responding on the cocaine lever in three of four monkeys. Naltrexone shifted the dose-response functions for heroin and its metabolites to the right, and in vivo apparent pA2 analyses revealed that naltrexone antagonized the effects of the opioids in a manner consistent with mu receptor antagonism (apparent pA2 values ranging from 8.20 to 8.47). Naltrindole only minimally altered the dose-response functions of heroin, 6-MAM, and morphine, whereas nor-binaltorphimine did not block the cocaine-like DS effects of the three opioid agonists, suggesting that neither delta nor kappa receptors played a prominent role in the cocaine-like DS effects of heroin and its metabolites.


CONCLUSIONS
These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.
Rowlett
J K
JK
Harvard Medical School, New England Regional Primate Research Center, Southborough, MA 01772, USA. james_rowlett@hms.harvard.edu
Spealman
R D
RD
Platt
D M
DM
D000701:Analgesics, Opioid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D003932:Heroin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000187:drug effects* / Q000502:physiology; D012453:Saimiri
D000701:Analgesics, Opioid; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; C051844:norbinaltorphimine; D009271:Naltrexone; D003932:Heroin; D003042:Cocaine