Published online before print June 18, 2007, doi: 10.1161/HYPERTENSIONAHA.107.091033
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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
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
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Opiate 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, µ-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 by µ- and -opioid receptor activation10 and by direct inhibition of rhythm-generating respiratory neurons in the pre-Botzinger complex.9,12,13
Respiratory neurons, including neurons in the pre-Botzinger complex, as well as CVNs, are modulated by serotonin.14 Serotonin enhances activity in respiratory neurons through its action on 5-hydroxytryptamine (5-HT)1A/7, 5-HT4, and 5-HT7 serotonin receptors.15 The contrasting actions of opioids and serotonin on respiratory neurons allow for the possibility that serotonergic receptor agonists could alleviate the depressive action of opioids. In recent neurophysiological investigations, the serotonergic ligands; 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT1A/7 and 5-HT7 serotonin receptors; and buspirone, a partial agonist at the 5-HT1A/7 receptor, reversed morphine-induced depression of respiratory neurons in anesthetized rats16 and goats.17 The 5-HT4 receptor agonists BIMU-8 and zacopride reversed opioid-induced depression of respiratory function and maintained fentanyl analgesia in anesthetized rats18 and immobilization in goats.17
Central 5-HT1A/7 receptors have also been shown to be involved in mediating both cardiopulmonary- and baroreceptor reflex–evoked changes in cardiac vagal activity but may not be involved in chemoreceptor-elicited responses in CVNs.19 However, the site(s) of activation of 5-HT receptors in the brain stem that mediate the changes in parasympathetic cardiac activity was not determined. Microinjection or iontophoretic application of different 5-HT agonists into the nucleus ambiguus has provided mixed responses. Although application of the 5-HT1A/7 agonist 8-OH-DPAT generally inhibit CVNs at a low dose of application, higher application doses elicited an excitation of CVNs.20 Other work has shown that microinjection of the 5-HT1A/7 agonist 8-OH-DPAT excited CVNs to evoke a bradycardia.21 Because little is known concerning the sites and mechanisms of action of 5-HT receptors on CVNs, and 5-HT1A/7 and 5-HT4 receptor activation show different effects on cardiorespiratory function and opioid depression, this study examines whether 5-HT1A/7 and 5-HT4 receptor agonists alter GABAergic neurotransmission to CVNs, as well as whether the opioid-mediated changes in spontaneous and respiratory-evoked neurotransmission to parasympathetic cardiac activity can be prevented by activation of 5-HT1A/7 and 5-HT4 receptors.
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Materials and Methods |
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Animal procedures and methodologies for identifying CVNs and recording from them in whole-cell patch clamp configuration with spontaneous rhythmic respiratory network activity are published as online supplemental data (http://hyper.ahajournals.org) and are identical to previously published methodologies.22 All of the animal procedures were performed with the approval of the animal care and use committee of George Washington University in accordance with the recommendations of the panel on euthanasia of the American Veterinary Medical Association and the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Focal drug application was performed with a PV830 Pneumatic PicoPump pressure delivery system (WPI), and GABAergic neurotransmission was isolated as described previously.23
µ-Opioid, 5-HT1A/7, and 5-HT4 Receptor Agonist Administration
Rhythmic inspiratory-related activity and inspiratory-evoked GABAergic synaptic inputs in CVNs were recorded simultaneously for 15 minutes in artificial cerebrospinal fluid. Slices were then exposed to the µ-opioid receptor agonist fentanyl by inclusion in the perfusate for 15 minutes. The exposure to fentanyl was then terminated, and the slice was perfused with the original artificial cerebrospinal fluid for 30 minutes.
Fentanyl was applied at a concentration of 1 or 5 nmol/L; these doses were chosen to be similar to the concentrations used in other studies of brain stem cardiorespiratory function.4,7 Each slice was exposed to 1 dose of fentanyl only. At the end of each experiment, respiratory evoked GABAergic activity was reversibly blocked with gabazine (25 µmol/L).
The 5-HT1A/7 receptor agonist 8-OH-DPAT18 was used at a dose of 5 µmol/L either alone or in combination with fentanyl. In a separate series of experiments, the 5-HT4 receptor agonist BIMU-818 was administered either alone or in combination with fentanyl at a concentration of 10 µmol/L. This drug was a generous gift from the Boehringer Ingelheim Pharma GmbH & Co.
In a separate series of experiments, miniature GABAergic inhibitory postsynaptic currents (mIPSCs) were isolated by inclusion of tetrodotoxin (1 µmol/L) in the perfusate to block action potential events. mIPSCs were recorded in the presence and absence of fentanyl (10 nmol/L) or coapplication of fentanyl (10 nmol/L) and BIMU-8 (10 µmol/L).
Data Analysis
Synaptic events were detected with MiniAnalysis 5.6.12 (Synaptosoft). Inhibitory postsynaptic current (IPSC) frequency was cross-correlated to the beginning of the inspiratory burst, including from 5 seconds before to 5 seconds after the onset of inspiratory activity. Spontaneous frequency was obtained from the 1-second period 4 to 5 seconds before the onset of inspiratory activity. All of the data are presented as averages ± SEM. Statistical comparisons were made with ANOVA with repeated measures and Newman-Keuls posttests and paired or unpaired Student’s t tests, as appropriate. P<0.05 indicated significant differences. Software used for statistics were Graphpad Prism 4.01 (Graphpad Software), Microcal Origin 6.0 (OriginLabs Corp), and Microsoft Excel (Microsoft Corp).
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Results |
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Effect of µ-Opioid Receptor Agonist Fentanyl and 5-HT1A/7 and 5-HT4
Receptor Agonists on Respiratory Activity in the Thick Medullary SliceFentanyl significantly inhibited inspiration burst frequency (Figure 1) but did not alter inspiratory amplitude or duration (data not shown). Inspiratory burst frequency decreased by 35±5.8% (n=8) and 40±7.3% (n=22) after 15 minutes of continuous application of fentanyl at concentrations of 1 and 5 nmol/L, respectively (Figure 1). The respiratory depression with opioids was reversible, because after termination of opioid application the frequency of respiratory bursts recovered in 10 to 20 minutes (Figure 1). There were no significant differences between the groups before drug application.
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0.01, and ***P
In contrast, the 5-HT1A/7 receptor agonist 8-OH-DPAT (5 µmol/L; n=10) significantly increased inspiratory bursting frequency by 25.5±7.8% (P<0.001; Figure 1). Administration of the 5-HT4 receptor agonist BIMU-8 (10 µmol/L; n=12) induced a slight increase in inspiratory bursting frequency (16±5.3%), although this increase was not statistically significant (P>0.05). Neither 8-OH-DPAT nor BIMU-8 changed inspiratory amplitude or duration (data not shown). Coapplication of either 8-OH-DPAT (5 µmol/L; n=9) or BIMU-8 (10 µmol/L; n=17) with fentanyl (5 nmol/L) prevented the fentanyl-induced respiratory depression and maintained a stable respiratory bursting frequency during the 60-minute experimental period (Figure 1).
Opioids Diminish Inspiratory-Evoked GABAergic Inhibitory Synaptic Inputs to CVNs
To determine the effects of opioids on inspiratory-evoked GABAergic inputs to CVNs, GABAergic neurotransmission was isolated by focal application of glycinergic and glutamatergic antagonists. On application of the µ-opioid receptor agonist fentanyl at a concentration of 1 nm, neither spontaneous nor the inspiratory-evoked GABAergic IPSC frequency significantly changed (n=8 cells; P>0.05 compared with control). However, application of fentanyl, at the higher dose of 5 nm, significantly inhibited both spontaneous GABAergic IPSC frequency and the increase in GABAergic frequency during inspiration (spontaneous GABAergic IPSC frequency: control [before fentanyl] 8.0±0.2 Hz, fentanyl 5 nm 6.6±0.3 Hz, P<0.001; inspiratory-evoked GABAergic IPSC frequency during burst: control 10.3±0.3 Hz, fentanyl 5 nm 8.6±0.3 Hz, n=9, P<0.001; Figure 2). The inhibitory action of fentanyl on GABAergic neurotransmission to CVNs during inspiration was reversible (Figure 2). All of the IPSCs under these recording conditions were blocked by the application of the GABAA antagonist gabazine (data not shown).
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XII) in this and all of the subsequent figures where appropriate, and GABAergic neurotransmission was isolated by focal application of N-methyl-D-aspartate, non–N-methyl-D-aspartate, and glycinergic receptor antagonists. In control conditions, the frequency of GABAergic IPSCs significantly increased during inspiratory bursts. After continuous and focal application of fentanyl (5 nmol/L; n=9), both spontaneous and inspiratory-evoked GABAergic IPSC frequency was significantly depressed. +++ denotes a statistically significant difference of P
Effect of 5-HT1A/7 Receptor Agonist 8-OH-DPAT and 5-HT4 Agonist BIMU-8 on Spontaneous and Inspiratory-Evoked GABAergic Inhibitory Synaptic Inputs to CVNs
Application of 5-HT1A/7 receptor agonist 8-OH-DPAT (5 µm; n=10) significantly inhibited spontaneous but not inspiratory-evoked GABAergic inhibitory synaptic neurotransmission to cardiac parasympathetic neurons in the nucleus ambiguus. Spontaneous GABAergic IPSC frequency decreased from control 9.6±0.8 Hz to 6.3±0.6 Hz (P=0.01; Figure 3) in the presence of 8-OH-DPAT. Inspiratory-evoked GABAergic inhibitory postsynaptic events were not significantly altered (control: 13.2±0.9 Hz; 8-OH-DPAT 5 µm: 12.6±1.0 Hz; P>0.05; Figure 3).
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To test whether 8-OH-DPAT could reverse fentanyl-induced inhibition of GABAergic neurotransmission to CVNs, 8-OH-DPAT (5 µm) was added into the perfusate with fentanyl (5 nmol/L). Coapplication of 8-OH-DPAT prevented the fentanyl-induced decrease in inspiratory-evoked GABAergic neurotransmitter release to cardiac parasympathetic neurons. Inspiratory-evoked GABAergic IPSC frequency maintained stable during the 60-minute experiment period (control: 12.8±0.6 Hz; 8-OH-DPAT 5 µm and fentanyl 5 nM: 11.6±0.6 Hz; n=9; P>0.05). However, spontaneous GABAergic IPSC frequency was still significantly decreased from control 9.1±0.7 Hz to 6.8±0.4 Hz (P=0.007) with 8-OH-DPAT and fentanyl coapplication (Figure 4).
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In contrast, bath application of the 5-HT4 agonist BIMU-8 (10 µm; n=12) alone did not alter GABAergic neurotransmission to CVNs (control: prebursting 9.8±0.7 Hz, during bursting 12.1±0.8 Hz; BIMU-8 10 µm: prebursting 9.1±0.7 Hz, during bursting 11.4±0.8 Hz). However, coapplication of fentanyl (5 nmol/L) and BIMU-8 (10 µmol/L; n=17) prevented the fentanyl-induced depression of both spontaneous and inspiratory-related GABAergic IPSC frequency (fentanyl 5 nm and BIMU-8 10 µm: spontaneous GABAergic IPSC frequency, 9.7±0.7 Hz; GABAergic IPSC frequency during bursting, 11.8±0.9 Hz; Figure 5).
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It is possible that BIMU-8 prevents the opioid-mediated depression of GABAergic neurotransmission by recruiting an additional and independent GABAergic pathway to CVNs and/or by preventing the inhibitory actions of µ-opioid receptor activation at presynaptic GABAergic terminals. To determine whether BIMU-8 can prevent the fentanyl-induced depression of GABAergic neurotransmission by acting at presynaptic terminals, GABAergic mIPSCs were examined. In the presence of tetrodotoxin, fentanyl (10 nmol/L) significantly reduced mIPSC frequency by 58±6% (see Figure 6; n=7; P<0.05). Coapplication of BIMU-8 (10 µmol/L) with fentanyl (10 nmol/L) prevented any significant change in GABAergic mIPSC frequency (Figure 6).
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Discussion |
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There are 4 major findings in this study. First, whereas the µ-opioid receptor agonist fentanyl induces a dose-dependent and reversible decrease in the frequency of respiratory bursting rate in the thick in vitro brain stem slice, the 5-HT1A/7 receptor agonist, 8-OH-DPAT, enhances respiratory activity, and both 8-OH-DPAT and the 5-HT4
receptor agonist, BIMU-8, prevent the µ-opioid–mediated respiratory-related depression. Second, both spontaneous and inspiratory-induced GABAergic neurotransmission to CVNs is inhibited by fentanyl. The 5-HT1A/7 receptor agonist, 8-OH-DPAT, also evokes a decrease in spontaneous but not inspiratory-evoked GABAergic postsynaptic neurotransmission to parasympathetic CVNs. Although coadministration of 8-OH-DPAT with fentanyl reversed the opioid-induced respiration-related depression and inspiratory-evoked GABAergic neurotransmitter input to parasympathetic CVNs, spontaneous GABAergic neurotransmission remained diminished with coapplication of 8-OH-DPAT and fentanyl treatment. Third, application of the 5-HT4 receptor agonist, BIMU-8, does not significantly alter either spontaneous or inspiratory-elicited GABAergic inhibitory postsynaptic inputs to cardiac parasympathetic neurons. However, BIMU-8 completely prevented the fentanyl-induced depression of both spontaneous and inspiratory-evoked GABAergic neurotransmission to CVNs. Our results also show that the BIMU-8 prevention of opioid inhibition can occur by interactions at the presynaptic GABAergic synaptic terminals. The results in this study demonstrate that activation of µ-opioid receptors induces a reversible decrease in the frequency of inspiratory bursting rate in the thick in vitro brain stem slice. These data are consistent with previous findings both in vivo and in vitro. Opioids suppress the frequency of neonatal rat respiration by likely acting on µ-opioid receptors located within regions of the ventral medulla containing respiratory rhythm-generating neurons localized to the pre-Botzinger complex. Although both inspiratory and preinspiratory neurons have been shown to be sufficient for respiratory rhythmogenesis, preinspiratory neurons are opioid insensitive.24 Because opioids inhibit the generation of inspiratory but not expiratory events, it has been proposed that pre-Botzinger neurons are responsible for inspiratory activity, whereas preinspiratory opioid-insensitive neurons may mediate primarily expiratory activity and/or the termination of inspiration.25 Our results are consistent with this hypothesis, because opioid receptor agonists decrease the inspiratory frequency, but not inspiratory amplitude or duration. Although the results in this study demonstrate that both 8-OH-DPAT and BIMU-8 can prevent µ-opioid–mediated respiratory depression on coapplication with fentanyl, future studies are warranted to examine whether 8-OH-DPAT and/or BIMU-8 can reverse pre-existing opioid-evoked respiratory depression.
In normal eupneic respiration, inspiration evokes an increase in the inhibitory GABAergic neurotransmission to CVNs,26 which likely mediates respiratory sinus arrhythmia. Spontaneous GABAergic activity to cardioinhibitory parasympathetic neurons originates, at least in part, from neurons located in the nucleus tractus solitarius.27 This spontaneous GABAergic activity is likely involved in cardiovascular reflexes, such as the baroreflex. The current study demonstrates that the µ-opioid receptor agonist fentanyl inhibits both spontaneous and inspiratory-evoked GABAergic synaptic inputs to CVNs. This may be a cellular mechanism responsible for opioid-induced bradycardia, blunted baroreceptor reflex, and decrease in respiratory sinus arrhythmia.
Central injections of 5-HT1A/7 agonists evoke a bradycardia, which is accompanied by an increase in respiration.28,29 Because 5-HT1A/7 receptors are likely inhibitory,20,30 this suggests the 5-HT1A/7 receptor–mediated decrease in heart rate is likely caused by disinhibition of parasympathetic cardioinhibitory neurons. Our results strongly support this hypothesis, because the 5-HT1A/7 receptor agonist 8-OH-DPAT inhibited spontaneous GABAergic inhibitory postsynaptic neurotransmission to parasympathetic CVNs. A major beneficial effect of 8-OH-DPAT is increased oxygen diffusion, likely by increased ventilation perfusion ratios.17 Our data provide a cellular basis for the beneficial effect of 8-OH-DPAT on cardiorespiratory ventilation-perfusion function, because 8-OH-DPAT differentially inhibits spontaneous GABAergic activity but does not change the increase in respiratory-evoked GABAergic inhibitory neurotransmission to cardiac parasympathetic neurons during inspiration that is responsible for respiratory sinus arrhythmia. Although activation of 5-HT1A/7 receptors by 8-OH-DPAT could reverse opioid-induced inhibition of respiration, it also produces a disinhibition of CVNs, similar to the effect of opioids; therefore, activation of both µ-opioid receptors and 5-HT1A/7 receptors in the brain stem depress spontaneous GABAergic neurotransmission to CVNs, likely resulting in increased activity of cardiac parasympathetic neurons in the nucleus ambiguus and a bradycardia.
A potentially clinically important finding of this study is that both depressed respiratory function and cardiorespiratory interactions by µ-opioid agonists can be prevented by administration of the 5-HT4 receptor agonist. Coadministration of the 5-HT4 receptor agonist BIMU-8 prevented the opioid-mediated depression of respiration and both spontaneous and respiratory related GABAergic neurotransmission to CVNs. Although it cannot be ruled out that BIMU-8 recruits an independent GABAergic pathway to CVNs that compensates for the reduced GABAergic transmission inhibited by opioids, our results examining GABAergic mIPSCs indicate that a more likely mechanism of action is that BIMU-8 occludes the effects of fentanyl at the presynaptic GABAergic synaptic terminal. This preventive effect is likely via competition of intracellular signaling pathways. It is possible that stimulation of the µ-opioid receptors decreases cAMP in GABAergic synaptic terminals, as well as inspiratory neurons,31 and consequently decreases GABAergic neurotransmission to CVNs and inspiratory drive, whereas stimulation of the 5-HT4 receptors would be predicted to increase cAMP and, thus, increase and restore GABAergic neurotransmission to CVNs and inspiratory drive.
Perspectives
The results in this study show that the 5-HT4 agonist BIMU-8 did not by itself enhance either respiration or GABAergic neurotransmission to CVNs; however, BIMU-8 did prevent the µ-opioid depression of both respiration and spontaneous and inspiratory-evoked GABAergic neurotransmission to CVNs. In contrast, the 5-HT1A/7 receptor agonist 8-OH-DPAT directly reduced spontaneous inhibitory postsynaptic GABAergic neurotransmitter input to parasympathetic CVNs and could not prevent the opioid-evoked inhibition of spontaneous GABAergic activity to CVNs. 5-HT receptor activation, especially 5-HT4 receptor agonists, may be a useful target to prevent respiratory depression and inhibition of respiratory sinus arrhythmia that occurs with µ-opioids.
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Acknowledgments |
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Sources of Funding
This work was supported by National Institutes of Health grant 59895 (to D.M.) and a Scientist Development Award from the American Heart Association (to X.W.).
Disclosures
None.
Received March 14, 2007; first decision April 4, 2007; accepted May 16, 2007.
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