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

Abstract

Abstract-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 -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 -opioidmediated 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-npropylamino)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. (Hypertention. 2007;50:368-376.)Key Words: heart rate Ⅲ parasympathetic Ⅲ serotonin Ⅲ opioid Ⅲ ambiguus Ⅲ GABA O piate exposure causes cardiorespiratory depression, including a centrally mediated bradycardia, respiratory inhibition, and a reduction in respiratory sinus arrhythmia. 1-3 Different opioid receptor agonists differentially enhance the activity of cardioinhibitory cardiac vagal neurons (CVNs) through disinhibition. More specifically, -opioid receptor agonists and nociceptin inhibit both spontaneous ␥-aminobutyric acid (GABA) and glycinergic synaptic inputs, 4 -7 whereas a -opioid agonist diminishes spontaneous glycinergic but not GABAergic neurotransmission to CVNs. 8 In vitro studies from both brain stem slice and brain stem-spinal cord preparations demonstrate that opioids decrease the frequency of respiratory activity. 9 -11 This opiate-induced depression of breathing is caused b...

5-HT1A/7receptor agonist excites cardiac vagal neurons via inhibition of both GABAergic and glycinergic inputs

“…Both the present study and a recent study by others [29] demonstrated that 8-OH-DPAT inhibited the GABAergic sIPSC of CVPN. The present study demonstrated that 8-OH-DPAT also inhibited the GABAergic currents of CVPN evoked by stimulation of the NTS.…”

“…This second possibility is supported by a previous study that found 5-HT, an endogenous non-selective agonist of 5-HT receptors, caused either an increase or a decrease of the sEPSC of DMV preganglionic neurons controlling the gastrointestinal tract [36] . It has also been indicated by Wang et al [29] that other subtype of 5-HT receptors, such as 5-HT 4α receptors, are involved in the control of the synaptic inputs of CVPN.…”

“…The fat pad of the heart contains the major cardiac parasympathetic ganglions, and neurons in these ganglions receive innervations from the terminals of CVPN [30] . The application of fluorescent tracers at the terminals of CVPN has been a well-established method to retrogradely label CVPN [29] . Special care was taken to avoid rhodamine leaking into the cardiac sac, which could lead to the mislabeling of the brain stem neurons innervating the tissues near the cardiac sac [31] .…”

“…At least some of the GABAergic inputs originate from the nucleus tractus solitarius (NTS) and can be activated by stimulation of this nucleus [28] ; the stimulationevoked GABAergic currents, compared with the spontaneous GABAergic synaptic currents, are commonly believed to be more closely related to the reflex control of these neurons. In a recent study, the 5-HT 1A/7 agonist was found to inhibit the spontaneous GABAergic synaptic currents of CVPN [29] , but its effect on the stimulation-evoked GABAergic currents has not been examined. In addition, whether the glycinergic inputs are also involved in the 5-HT receptormediated excitation of CVPN is not known.…”

Sources of Inspiration: A Neurophysiologic Framework for Understanding Anesthetic Effects on Ventilatory Control

“…More than a decade later, Sahibzada et al [45] found that buspirone as well as another 5-HT1 A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), reverses morphine-induced apnea in both spontaneously breathing and mechanically ventilated, anesthetized rats. In brainstem slices, Wang et al [46] found that both 8-OH-DPAT and BIMU-8, an agonist of the 5-HT4a receptor, prevent fentanyl-induced respiratory depression. Recently, Guenther et al [47] showed that 8-OH-DPAT and another 5-HT1 A receptor agonist, repinotan, stimulate ventilation in a dose-dependent fashion in brainstem-spinal cord preparations as well as in anesthetized rats [48,49 •• ].…”