Abstract
In opioid-dependent subjects, the low-efficacy μ agonist nalbuphine generally precipitates withdrawal or withdrawal-like stimulus effects. To provide a more complete characterization of the discriminative stimulus effects of nalbuphine in opioid-treated subjects, seven White Carneux pigeons were treated daily with 10 mg/kg morphine i.m. and trained 6 h later to discriminate among 10 mg/kg morphine, 1.0 mg/kg nalbuphine, and saline by responding on one of three different keys. When tested, morphine produced morphine-key responding and nalbuphine produced nalbuphine-key responding. Replacing the daily morphine injection with saline produced nalbuphine-key responding, and this effect was reversed by the administration of morphine. In substitution tests with other compounds, the antagonists naltrexone (i.m.) and CTAP (d-Phe-Cys-Tyr-d-Tryp-Lys-Thr-Pen-Thr-NH2) (i.c.v.) produced nalbuphine-key responding. High-efficacy agonists fentanyl and etorphine produced morphine-key responding. The intermediate-efficacy agonists buprenorphine, dezocine, and butorphanol produced a pattern of morphine-, saline-, and/or nalbuphine-key responding that differed across individual pigeons. The lower efficacy agonists nalorphine and levallorphan produced predominantly nalbuphine-key responding. The κ agonists spiradoline and U50,488 [trans-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate], the nonopioid d-amphetamine, and saline produced predominantly saline-key responding. Naltrexone and nalbuphine dose dependently reversed the morphine-key responding produced by the training dose of morphine. Together, these data suggest that the discriminative-stimulus effects of the low-efficacy μ agonist nalbuphine in morphine-treated pigeons are similar to those of other low-efficacy agonists, naltrexone, and the termination of daily morphine treatment.
Footnotes
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This research was supported by National Institute on Drug Abuse Grants DA10776 (to E.A.W.), DA10277 (to M.J.P.), and DA02749 (to L.A.D.). A portion of these data were presented and published as a part of the Fifth International Meeting on Drug Discrimination, Beerse, Belgium, August 1998 (Pharmacol Biochem Behav64:445–448, 1999).
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DOI: 10.1124/jpet.103.058503.
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ABBREVIATIONS: FR, fixed ratio; CL, confidence limits; CTAP, d-Phe-Cys-Tyr-d-Tryp-Lys-Thr-Pen-Thr-NH2; DAMGO, [d-Ala2, N-Me-Phe4,Gly5-ol]-enkephalin; SNC80, (+)-4-[(αR)-α-[2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl]-3-methoxybenzyl]-N,N-diethylbenzamide; U50,488, trans-3,4-di-chloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl)benzeneacetamide methanesulfonate.
- Received August 11, 2003.
- Accepted March 25, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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