Reversal of morphine-induced apnea in the anesthetized rat by drugs that activate 5-hydroxytryptamine(1A) receptors

The purpose of our study was to test the hypothesis that 5-hydroxytryptamin e (5-HT)(1A) receptor agonists counteract morphine-induced respiratory depr ession. Studies were conducted in anesthetized rats, and respiratory activi ty was monitored with diaphragm electromyography. Morphine was administered i.v. in doses that produce apnea. Once apnea was established, i.v. adminis tration of the 5-HT1A receptor agonist drug 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) at 10 or 100 mg/kg restored normal breathing in each a nimal (n = 24). This antagonistic effect of 8-OH-DPAT on morphine-induced r espiratory depression was observed in both spontaneously breathing and arti ficially ventilated animals. Results obtained with 8-OH-DPAT were mimicked by buspirone (50 mg/kg i.v.), another 5-HT1A receptor agonist drug. Pretrea tment with 4-(2'-methoxyphenyl)-1-[2'[N-(2'-pyridinyl]-p-iodo-benzamido]eth yl]piperazine, an antagonist of 5-HT1A receptors, prevented 8-OH-DPAT from counteracting morphine-induced apnea. These results indicate that activatio n of central nervous system 5-HT1A receptors is an effective way of reversi ng morphine-induced respiratory depression. Most important, this is the thi rd model of disturbed respiratory function in which drugs that stimulate 5- HT1A receptors have been shown to restore breathing to near-normal levels.