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Vol. 292, Issue 2, 704-713, February 2000

Reversal of Morphine-Induced Apnea in the Anesthetized Rat by Drugs that Activate 5-Hydroxytryptamine1A Receptors1

Niaz Sahibzada , Manuel Ferreira, Adam M. Wasserman, Angelo M. Taveira-DaSilva and Richard A. Gillis

Department of Pharmacology, Georgetown University Medical Center, Washington, DC (N.S., M.F., A.M.W., A.M.T., R.A.G.); and Department of Psychology, University of the District of Columbia, Washington, DC (N.S.).

The purpose of our study was to test the hypothesis that 5-hydroxytryptamine (5-HT)1A receptor agonists counteract morphine-induced respiratory depression. Studies were conducted in anesthetized rats, and respiratory activity was monitored with diaphragm electromyography. Morphine was administered i.v. in doses that produce apnea. Once apnea was established, i.v. administration of the 5-HT1A receptor agonist drug 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) at 10 or 100 µg/kg restored normal breathing in each animal (n = 24). This antagonistic effect of 8-OH-DPAT on morphine-induced respiratory depression was observed in both spontaneously breathing and artificially ventilated animals. Results obtained with 8-OH-DPAT were mimicked by buspirone (50 µg/kg i.v.), another 5-HT1A receptor agonist drug. Pretreatment with 4-(2'-methoxyphenyl)-1-[2'[N-(2'-pyridinyl]-p-iodo-benzamido]ethyl]piperazine, an antagonist of 5-HT1A receptors, prevented 8-OH-DPAT from counteracting morphine-induced apnea. These results indicate that activation of central nervous system 5-HT1A receptors is an effective way of reversing morphine-induced respiratory depression. Most important, this is the third model of disturbed respiratory function in which drugs that stimulate 5-HT1A receptors have been shown to restore breathing to near-normal levels.

1 This study was supported by National Institutes of Health Grants NS36035 and GM08005 (N.S.) and NS28130 (R.A.G.), as well as a Research Supplement Award for Underrepresented Minorities (M.F.) and National Institutes of Health Predoctoral Fellowship DA005889 (A.M.W.).

0022-3565/00/2922-0704$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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