Abstract
Naltrexone (NTX) exhibited approximately 3-fold higher affinity for sites labeled by [3H]U69,593 (putative κ1-selective ligand) than [3H]bremazocine (non-selective ligand) in the presence of mu anddelta receptor blockade in monkey brain membranes. This led us to test an hypothesis that NTX could display in vivo antagonist selectivity for κ1-versus non-κ1-mediated effects. Six opioid agonists were characterized by NTX apparent pA2 analysis in a 50°C water tail-withdrawal assay in rhesus monkeys. Constrained NTX pA2 values (95% confidence limits) were: alfentanil, 8.66 (8.47–8.85); ethylketocyclazocine, 7.97 (7.93–8.01); U69,593, 7.64 (7.49–7.79); U50,488, 7.55 (7.42–7.67); bremazocine, 6.92 (6.73–7.12); enadoline, 6.87 (6.69–7.05). Pretreatment with clocinnamox, an irreversible mu antagonist, confirmed that mu receptors were not involved in the antinociception produced by the kappa agonists, U69,593, U50,488, bremazocine and enadoline; however, both mu andkappa receptors mediated the antinociceptive effects of ethylketocyclazocine. The apparent NTX pA2 profile of opioid agonists correlated highly with the radioligand binding studies, which indicates that U69,593 and U50,488 produced antinociception by acting on kappa-1 receptors, whereas bremazocine and enadoline probably acted via non-kappa-1 receptors. This study provides further functional evidence ofkappa opioid receptor multiplicity in primates and suggests that NTX may be a useful tool to study this phenomenonin vivo.
Footnotes
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Send reprint requests to: Dr. James H. Woods, Department of Pharmacology, Medical School, University of Michigan, 1301 MSRB III, Ann Arbor, MI 48109-0632.
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↵1 Animals used in these studies were maintained in accordance with the University Committee on the Use and Care of Animals, University of Michigan, and Guidelines of the Committee on the Care and Use of Laboratory Animals of the institute of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, Publication ISBN 0–309-05377–3, revised 1996).
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↵2 This research was supported by USPHS Grant 00254. Preliminary results were presented at the 59th annual meeting of the College on Problems of Drug Dependence, Nashville, TN, 1997.
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↵3 Present address: Rockefeller University, New York, NY
- Abbreviations:
- C-CAM
- clocinnamox
- Enadoline
- CI-977
- DR
- dose ratio
- EKC
- ethylketocyclazocine
- NTX
- naltrexone
- %MPE
- %maximum possible effect
- DAMGO
- [d-Ala2,(Me)Phe4,Gly(ol)5]enkephalin
- DPDPE
- [d-Pen2,d-Pen5]enkephalin
- β-FNA
- β-funaltrexamine
- Received August 29, 1997.
- Accepted January 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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