Abstract
This study characterized the antinociceptive, respiratory and heart rate effects of the cannabinoid receptor agonists Δ-9-tetrahydrocannabinol (Δ-9-THC) and WIN 55212 {(R)-(+)-2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrol-[1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphtalenyl)methanone monomethanesulfonate}, N-arachidonyl ethanolamide (anandamide) and the mu and kappa opioid receptor agonists heroin and U69593, alone and in conjunction with a cannabinoid receptor antagonist, SR 141716A [N-(piperidin-1–1-yl)-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride] and an opioid receptor antagonist, quadazocine, in rhesus monkeys (Macaca mulatta). Using 12 adult rhesus monkeys, latencies to remove the tail from a 50°C water bath, respiration in 5% CO2 and heart rate were measured. When administered alone, SR 141716A (1.8, 5.6 mg/kg i.m.) did not alter nociception, respiration or heart rate. Δ-9-THC (0.1–10 mg/kg i.m.) and WIN 55212 (0.1–10 mg/kg i.m.) dose-dependently increased antinociception and dose-dependently decreased respiratory minute and tidal volumes and heart rate. These antinociceptive, respiratory and heart rate effects were reversed by SR 141716A but not by the opioid antagonist quadazocine (1 mg/kg i.m.). Anandamide (10 mg/kg i.m.) also produced antinociception. Heroin (0.01–10 mg/kg i.m.) and U69593 (0.01–3.2 mg/kg i.m.) also dose-dependently increased antinociception and decreased respiratory and heart rate measures; these effects were antagonized by quadazocine but not by SR 141716A. These results demonstrate selective and reversible antagonism of cannabinoid behavioral effects by SR 141716A in rhesus monkeys.
Footnotes
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Send reprint requests to: Dr. J. A. Vivian, Department of Pharmacology, University of Michigan Medical School, 1301 MSRB III, Ann Arbor, MI 48109-0632. E-mail:jvivian{at}umich.edu
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↵1 This work was supported by United States Public Health Service Grants DA00254, DA07268, DA05773 and GM07767.
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↵2 Animals used in these studies were maintained in accordance with the University of Michigan Committee on Animal Care and Guidelines of the Committee on the Care and Use of Laboratory Animal Resources, National Health Council (Department of Health, Education and Welfare, ISBN 0–309-05377–3, revised 1996).
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↵3 Present address: Department of Pharmacology, Wakayama Medical College, 9-Banch 27, Wakayama-city, Wakayama 640, Japan.
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↵4 Present address: Box 171, Rockefeller University, 1230 York Avenure, New York, NY 10021.
- Abbreviations:
- Δ-9-THC
- Δ-9-tetrahydrocannabinol
- Δ-8-THC
- Δ-8-tetrahydrocannabinol
- f
- frequency
- Ve
- minute volume
- Vt
- tidal volume
- Received November 4, 1997.
- Accepted April 9, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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