Abstract
κ-Opioid agonists may functionally antagonize some behavioral effects of cocaine, but the role of mixed κ/μ receptor activity is unclear. The effects of three mixed κ/μ agonists (MCL-101, (−)cyclorphan, and Mr2034) and one κ-selective agonist (enadoline) on cocaine self-administration and cocaine discrimination were compared in rhesus monkeys. Acute treatment with all κ 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 κ/μ agonists produced fewer side effects (some salivation) than the κ-selective agonist (sedation, salivation, emesis). However, none of these κ 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, κ and mixed κ/μ-opioid agonists may reduce cocaine self-administration without altering cocaine's discriminative stimulus effects. Mixed κ/μ agonists appear to offer some advantages over selective κ agonists as potential treatments for cocaine abuse.
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Acknowledgements
The capable technical assistance of Bregiete Luinge and Raoul Fisser in the synthesis of (−)cyclorphan and MCL-101 is gratefully acknowledged. We thank Mallinckrodt, Inc., for generously donating levorphanol tartrate. We thank Inge Knudson for excellent assistance with the graphic displays. Preliminary results were presented at the annual meeting of the College on Problems of Drug Dependence, 1999, and the International Narcotics Research Conference, 2001. This work was supported by Grants U19-DA11007, R01-DA02519, K05-DA00101, T32-DA07252, and K05-DA00360 from the National Institute on Drug Abuse, National Institutes of Health.
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Bowen, C., Stevens Negus, S., Zong, R. et al. Effects of Mixed-Action κ/μ Opioids on Cocaine Self-Administration and Cocaine Discrimination by Rhesus Monkeys. Neuropsychopharmacol 28, 1125–1139 (2003). https://doi.org/10.1038/sj.npp.1300105
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DOI: https://doi.org/10.1038/sj.npp.1300105
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