Abstract
The opioid agonists morphine, etorphine, buprenorphine and U50,488 were examined alone and in combination with the insurmountable opioid antagonist clocinnamox (C-CAM) in squirrel monkeys responding under a schedule of shock titration. In this procedure, shock intensity increased every 15 sec from 0.01 to 2.0 mA in 30 increments. Five lever presses during any given 15-sec shock period produced a 15-sec timeout, after which shock resumed at the next lower intensity. When given alone, each of these agonists increased the median intensity at which the monkeys maintained shock [median shock level (MSL)]. At the highest dose examined alone, each agonist produced maximal increases in MSL and, except buprenorphine, decreased response rates. C-CAM dose-dependently antagonized the effects of morphine, etorphine and buprenorphine on MSL. In the presence of the higher C-CAM doses, etorphine, morphine and buprenorphine did not produce maximal effects on MSL. The effects of U50,488 were not systematically altered when tested in combination with the highest C-CAM dose. In general, C-CAM was more potent and the duration of antagonism was slightly longer against buprenorphine than against morphine and etorphine. Quantitative analysis of these data according to an extended model of Black and Leff [(1983) Proc R Soc Lond B Biol 220:141–162]yielded the following apparent affinity and efficacy estimates, respectively: etorphine (0.085 mg/kg, 117); morphine (49 mg/kg, 24) and buprenorphine (0.62 mg/kg, 7.1). Determination of the individual q values over time indicated that the receptor population recovers more quickly after C-CAM antagonism of etorphine than from C-CAM antagonism of either morphine or buprenorphine. These data suggest that C-CAM functions as a long-lasting antagonist of mu opioid agonist actions in a shock titration procedure and yields estimates of relative intrinsic efficacy with the rank order of etorphine > morphine > buprenorphine.
Footnotes
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Send reprint requests to: Raymond C. Pitts, Ph.D., Department of Psychology, University of North Carolina at Wilmington, 601 S. College Rd., Wilmington, NC 28403-3297.
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↵1 This research was supported by United States Public Service Grant DA02749 from the National Institute on Drug Abuse. Animals used in this study were cared for in accordance with the guidelines of the Institutional Animal Care and Use Committee of the University of North Carolina, and the “Guide for the Care and Use of Laboratory Animals” (Department of Health and Human Services, National Institutes of Health, Publication No. 85–23, revised 1985).
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↵2 Current address: Psychology Department, University of North Carolina at Wilmington, 601 S. College Rd., Wilmington, NC 28403-3297.
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↵3 Recipient of Research Scientist Award DA00033 from the National Institute on Drug Abuse.
- Abbreviations:
- β-FNA
- β-funaltrexamine
- C-CAM
- clocinnamox
- U50
- 488,trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide
- MSL
- median shock level
- FR
- fixed-ratio
- R/sec
- responses per second
- Received September 8, 1997.
- Accepted February 27, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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