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(Hypertension. 2007;50:368.)
© 2007 American Heart Association, Inc.

Original Articles

5-Hydroxytryptamine 1A/7 and 4 Receptors Differentially Prevent Opioid-Induced Inhibition of Brain Stem Cardiorespiratory Function

Xin Wang; Olga Dergacheva; Harriet Kamendi; Christopher Gorini; David Mendelowitz

From the Department of Pharmacology and Physiology, George Washington University, Washington, DC.

Correspondence to David Mendelowitz, Department of Pharmacology and Physiology, George Washington University, 2300 Eye St, NW, Washington, DC 20037. E-mail dmendel{at}gwu.edu

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and -aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The µ-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4 agonist BIMU-8 did not by itself change inspiratory activity but prevented the µ-opioid–mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5-hydroxytryptamine receptors, particularly 5-hydroxytryptamine 4 agonists, may be a useful therapeutic approach in preventing opioid-evoked cardiorespiratory depression.

Key Words: heart rate • parasympathetic • serotonin • opioid • ambiguus • GABA