Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys

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Abstract
-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed / receptor activity is unclear. The effects of three mixed / agonists (MCL-101, (-)cyclorphan, and Mr2034) and one -selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all agonists dose dependently reduced cocaine-maintained responding and produced a downward shift in the cocaine self-administration dose–effect curve (0.001–0.32 mg/kg/inj, i.v.). During 7 days of chronic treatment, (-)cyclorphan (0.0032–0.032 mg/kg/h) and MCL-101 (0.0032–0.032 mg/kg/h) each dose dependently reduced cocaine self-administration maintained by a dose near the peak of the cocaine self-administration dose–effect curve. MCL-101 (0.032 mg/kg/h) produced selective and sustained decreases in cocaine self-administration, whereas (-)cyclorphan (0.032 mg/kg/h) had selective but transient effects. In addition, these mixed / agonists produced fewer side effects (some salivation) than the -selective agonist (sedation, salivation, emesis). However, none of these agonists substituted for or antagonized cocaine's discriminative stimulus effects in monkeys trained to discriminate cocaine (0.4 mg/kg, i.m.) from saline. Thus, and mixed /-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed / agonists appear to offer some advantages over selective agonists as potential treatments for cocaine abuse.