J K Rowlett1, R D Spealman, D M Platt. 1. Harvard Medical School, New England Regional Primate Research Center, Southborough, MA 01772, USA. james_rowlett@hms.harvard.edu
Abstract
RATIONALE AND OBJECTIVES: 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.
RATIONALE AND OBJECTIVES: 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.
Authors: Jeremy C Cornelissen; Samuel Obeng; Kenner C Rice; Yan Zhang; S Stevens Negus; Matthew L Banks Journal: J Pharmacol Exp Ther Date: 2018-01-12 Impact factor: 4.030