Abstract
Squirrel monkeys were trained to discriminate i.m. injections of the κ-opioid receptor agonist enadoline (0.0017 mg/kg) from saline in a two-lever drug-discrimination procedure. Enadoline produced a reliable discriminative stimulus that was reproduced by the κ-selective agonists PD 117302, U 50,488, GR 89686A, (−)-spiradoline, ICI 204448, and EMD 61753, and by the mixed-action κ/μ-agonists bremazocine and ethylketocyclazocine. The discriminative stimulus effects of enadoline were not reproduced by the μ-selective agonist morphine, the δ-selective agonist BW373U86, the mixed-action opioids nalbuphine and nalorphine, or by the less active enantiomers of enadoline and spiradoline PD 129829 and (+)-spiradoline, respectively. The selective μ-opioid antagonist β-funaltrexamine (10.0 mg/kg) did not appreciably alter the dose-effect function for enadoline in any subject. However, the nonselective and κ-selective opioid antagonists quadazocine (0.03–3.0 mg/kg) and nor-BNI (3–10 mg/kg), and the mixed-action opioid nalbuphine (0.3–30 mg/kg) served to surmountably antagonize enadoline's discriminative stimulus effects. The antagonist effects of nor-BNI were long-lasting and did not distinguish between drugs purported to act at different κ-receptor subtypes. The present results bolster the view that common discriminative stimulus effects of enadoline and other opioids are mediated by κ-agonist actions that are surmountably antagonized by nor-BNI in a long-lasting manner. The enadoline-antagonist effects of nalbuphine support the idea that it acts with low efficacy at κ-opioid receptors.
Footnotes
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Send reprint requests to: Dr. Jack Bergman, Harvard Medical School, McLean Hospital ADARC, 115 Mill St., Belmont, MA 02478. E-mail:jbergman{at}hms.harvard.edu
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This work was conducted at the New England Regional Primate Research Center and supported by U.S. Public Health Service Grants MH07658, DA 03774, and RR00168. Animals used in this study were maintained in accordance with the guidelines of the Committee on Animals of the Harvard Medical School and of the Guide for Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council, Department of Health, Education, and Welfare, Publication (National Institutes of Health) 85-23 (revised 1985).
- Abbreviations:
- EKC
- ethylketocyclazocine
- β-FNA
- β-funaltrexamine
- nor-BNI
- nor-binaltorphimine
- FR
- fixed ratio
- TO
- time-out
- Received August 14, 2000.
- Accepted December 7, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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