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The Counteraction of Opioid-Induced Ventilatory Depression by the Serotonin 1A-Agonist 8-OH-DPAT Does Not Antagonize Antinociception in Rats In Situ and In Vivo

Guenther, Ulf, MD*; Manzke, Till, PhD; Wrigge, Hermann, PhD*; Dutschmann, Matthias, PhD; Zinserling, Joerg, PhD*; Putensen, Christian, PhD*; Hoeft, Andreas, PhD*

doi: 10.1213/ane.0b013e318198f828
Anesthetic Pharmacology: Research Reports
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BACKGROUND: Spontaneous breathing during mechanical ventilation is gaining increasing importance during intensive care but is depressed by narcotics, such as opioids. Serotonin 1A-receptor (5-HT1A-R) agonists have been shown to antagonize opioid-induced ventilatory depression, but both enhancement and attenuation of nociceptive reflexes have been found with different experimental models. To clarify contradictory findings, we simultaneously determined dose-response functions of the standard 5-HT1A-R-agonist 8-OH-DPAT and two different opioids for spontaneous ventilation and nociception. Two hypotheses were tested: 1) 8-OH-DPAT at a dose to stimulate spontaneous breathing does not activate nociceptive reflexes. 2) 8-OH-DPAT does not diminish opioid-induced antinociception.

METHODS: (A) A dose-response relationship of 8-OH-DPAT, spontaneous phrenic nerve activity and a nociceptive C-fiber reflex (CFR) were established simultaneously in an in situ perfused, nonanesthetized, rat brainstem-spinal cord preparation. (B) Fentanyl was administered in situ to investigate the interaction with 8-OH-DPAT on phrenic nerve activity and nociceptive CFR. Additional experiments involved the selective 5-HT1A-R-antagonist WAY 100 635 to exclude effects of receptors other than 5-HT1A-R. (C) The effects of 8-OH-DPAT on spontaneous ventilation and nociceptive tail-flick reflex with and without morphine were verified in in vivo anesthetized rats.

RESULTS: Low-dose 8-OH-DPAT (0.001 and 0.01 μM in situ, 0.1 μg/kg in vivo) enhanced nociceptive reflexes but did not activate spontaneous ventilation. On the contrary, high doses of 8-OH-DPAT (1 μM in situ and 10–100 μg/kg in vivo) stimulated ventilation, whereas nociceptive CFR amplitude in situ returned to baseline and tail-flick reflex was depressed in vivo. Opioid-induced ventilatory depression was antagonized by 8-OH-DPAT (1 μM in situ, and 10 μg/kg in vivo), whereas antinociception sustained. Selective 5-HT1A-R-antagonist WAY 100 635 (1 μM) prevented the effects of 8-OH-DPAT in situ.

CONCLUSION: 5-HT1A-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception in rats.

IMPLICATIONS: The serotonin 1A-receptor agonist 8-OH-DPAT, at a dose sufficient to stimulate spontaneous breathing, does not activate nociceptive reflexes, and it counteracts opioid-induced ventilatory depression without diminishing antinociception in rats.

From the *Clinic of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany; and †DFG Research Center Molecular Physiology of the Brain (CMPB), Goettingen, Humboldtallee 23, Goettingen, Germany.

Accepted for publication December 10, 2008.

Ulf Guenther and Till Manzke contributed equally to this work.

Supported by Departmental Funds.

Address correspondence and reprints request to Ulf Guenther, MD, DESA, EDIC; Clinic of Anesthesiology and Intensive Care, University Hospital of Bonn, Sigmund-Freud-St. 25, D-53105 Bonn, Germany. Address e-mail to ulf.guenther@ukb.uni-bonn.de.

Opioids are the most powerful analgesics to treat severe pain during anesthesia, critical care, and pain therapy, but their administration is always limited by the risk of apnea.1–5 Fatal incidents still occur,6,7 so opioid pain therapy must often be balanced against ventilatory depression. Moreover, spontaneous breathing during mechanical ventilation in critical care medicine has been shown to increase splanchnic and renal blood flow and to reduce ventilator time and length of stay in the intensive care unit.8–11 A pharmacological substance to activate spontaneous breathing could thus contribute to improving patients’ hemodynamics and decreasing treatment costs.

The serotonin receptor (5-HT-R) system consists of many subtypes, two of which are capable of activating spontaneous breathing: 5-HT4-R-agonist BIMU-8 was found to counteract opioid-induced ventilatory depression without impairing antinociception in situ and in vivo rats.12 Because of the severe cardiac side effects of 5-HT4-R-agonists,13,14 we did not investigate this class of substance any further. 5-HT1A-R agonists have also been demonstrated to activate spontaneous breathing15,16 and were successfully involved in the treatment of severe ventilatory dysfunction because of brainstem damage in humans.17,18 Most notably, it was shown that the partial 5-HT1A-R-agonists buspirone and the selective 5-HT1A agonist 8-OH-DPAT could even compensate for opioid-induced ventilatory depression.19,20

A major drawback for clinical use of 5-HT1A-R-agonists to antagonize opioid effects would be an increase in pain sensation. Indeed, both augmentation21,22 and attenuation of nociception23–25 have been reported. Others, who reported on the ventilatory stimulation by 8-OH-DPAT, did not investigate nociception.19 The contradictory published data are at least, in part, attributable to different experimental setups, dosing ranges, administration routes, and time course of applied substances.22,26–29 Hence, two different models and large dosing ranges were chosen for this investigation.

The aim of this study was to determine the dose at which the standard 5-HT1A-R-agonist 8-OH-DPAT sufficiently stimulates spontaneous breathing and whether 8-OH-DPAT interferes with opioid-induced antinociception in an in situ perfused brainstem spinal cord (PBSC) rat model and in in vivo anesthetized rats. Two hypotheses were tested: 1) 8-OH-DPAT at a dose to stimulate spontaneous breathing does not enhance nociceptive reflexes. 2) Stimulation of spontaneous breathing by 8-OH-DPAT does not diminish opioid-induced antinociception.

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METHODS

Experiments were approved by the local council of ethics and performed in accordance with the Guidelines for the Care and Use of Laboratory Animals adopted from the United States National Institute of Health. Animals were housed in standard laboratory conditions with a 12-h light: dark schedule and free access to food and water. The in situ PBSC preparation has been adopted from J.F. Paton’s working heart-brainstem preparation.30–32 It retains in vivo-like spontaneous phrenic nerve activity as a measure for spontaneous breathing,33,34 but does not require anesthetics and offers constant Pco2-levels. Moreover, it allows for recording of nociceptive reflex loops, such as the straighten reflex, without interference with narcotics.12 To represent the clinical situation with varying Pco2-levels and narcotics in spontaneously breathing patients, experiments were reproduced in vivo with anesthetized, spontaneously breathing rats. For a constant opioid effect in vivo, morphine was chosen.

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In Situ PBSC

Detailed descriptions of the in situ and in vivo methods were given elsewhere.12 In brief, 40 juvenile Sprague-Dawley rats (age 21–28 days, 70 ± 3 g) were deeply anesthetized with sevoflurane, decerebrated, and transected below the diaphragm. The descending aorta was cannulated and perfused with electrolyte solution, supplemented with 10 mmol d-glucose and poly(-sucrose-co-epichlorhydrin) (Ficoll pm 70®, Sigma-Aldrich, Munich, Germany) to maintain colloid osmotic pressure. Aerated with carbogen (95% O2/5% CO2) at 30°C, pH was adjusted to 7.35. The phrenic nerve signal was recorded with a monopolar suction electrode, amplified, bandpass filtered (1.5–2.5 kHz), rectified, and integrated. As an index for minute ventilation (MV), the phrenic nerve minute activity was calculated from the area under the curve of integrated phrenic nerve signal and summed up over 1 min. Nociception was established by a nociceptive C-fiber reflex (CFR) loop. The left median nerve was electrically stimulated at the level of the wrist to evoke the straighten reflex of the right forepaw. The reflex response was recorded with a suction electrode from a branch of the thoracolateral nerve innervating part of the extension musculature, as has been previously described.12 The responses to 20 sweeps of single square pulses (0.2 ms, 5–15 V, every 10 s) were recorded and averaged. Stimulation protocol has been adopted from previous work in our institute.35,36 Voltage was set as low as possible to elicit a reflex response. In preliminary experiments, this reflex proved to be mainly resistant to tetodrodotoxin, which excludes Ad-fibers to be involved, and nociceptive C-fibers to conduct the predominant part of the reflex.36,37

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In Vivo Anesthetized Rat

Twelve male Sprague Dawley rats (258 ± 8 g) were deeply anesthetized with sodium-pentobarbitone (60 mg/kg) intraperitoneally and placed supine on a heating pad. The right inguinal artery and vein were cannulated via a small surgical incision, and an arterial catheter was connected to a pressure-transducer to continuously monitor mean arterial blood pressure (MAP) and obtain blood gas analyses. A rectal temperature probe was inserted, and body temperature was kept constant at 37°C ± 0.5°C. Animals breathed spontaneously via a tracheostomy tube (inner diameter 1.2 mm). A small animal ventilator (KTR-4, Hugo Sachs Elektronik, March, Germany) allowed for mechanical ventilation in case of accidental apnea. Anesthesia was maintained with sevoflurane, leveled at an inspiratory concentration of 1.5–2.5 Vol% to ensure immobility and stable spontaneous breathing and tail-flick reflex (TFR). The expired air was lead through a pneumotachograph (ADInstruments GmbH, Spechbach, Germany) to record respiratory rate, calculate tidal volume, and minute volume (MV) by integration of ventilatory airflow over time.

The TFR was evoked by a 100-W light beam source mounted 15 mm over the base of the tail to reach maximum temperature in less than a second. The resulting reflex response was recorded by a strain gauge attached to the tail distal to the heating spot. Heating was stopped when the tail flicked or a maximum of 15 s were reached to prevent damage. Three sweeps were recorded and averaged. The blood pressure transducer, pneumotachograph, temperature probe, and strain-gauge transducer were connected to an A/D-interface (PowerLab 4/25®, ADInstruments GmbH, Spechbach, Germany).

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Drug Application Protocols (Fig. 1 for Schematic Overview)

Figure 1.

Figure 1.

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In Situ

5-HT1A-R-agonist (±)-8-OH-DPAT-hydrobromide (8-OH-DPAT) was applied to the perfusion solution, cumulatively at increasing doses (n = 8, Fig. 1), followed by the selective 5-HT1A-R-antagonist WAY 100 635-maleate (1 μM, both: Sigma-Aldrich Chemicals, Munich, Germany). The effects of WAY 100 635 alone were tested in another series (n = 6); NaCl 0.9% (application of drug vehicle only) served as controls (n = 6).

Fentanyl (Janssen-Cilag GmbH, Neuss, Germany) was administered to depress spontaneous phrenic nerve frequency by >50% of the pretreatment level. 8-OH-DPAT was added at increasing doses thereafter (n = 6) or NaCl 0.9% for controls (n = 6). Experiments were completed either by the opioid-antagonist naloxone 1 μM (Ratiopharm GmbH, Ulm, Germany) or by a 500 mL one-way washout of substances with perfusion solution, to verify integrity of the nociceptive reflex loop.

In another series, fentanyl was first followed by 5-HT1A-R-antagonist WAY 100 635, then by 8-OH-DPAT (0.1 μM, 1 μM; n = 5) or NaCl 0.9% for controls (n = 4). The WAY 100 635 dosage was derived from previous publications22,38 and adapted to the higher 8-OH-DPAT dosing in this study.

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In Vivo

8-OH-DPAT was given IV, cumulatively at increasing doses (0.1, 1, 10, 100 μg/kg; n = 6) or NaCl 0.9% for controls (n = 6).

Morphine (Merck KGaA, Darmstadt, Germany) was injected to depress ventilatory frequency by >50% of the pretreatment level. 8-OH-DPAT was given cumulatively at increasing doses (0.1, 1, 10, 100 μg/kg; n = 6) subsequently or NaCl 0.9% for controls (n = 6). Naloxone-HCl (1 mg/kg) was added at the conclusion of experiments to verify the integrity of TFR.

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Data Analysis and Statistical Procedures

Data were analyzed with Chart 4.0 and Scope 4.0 software package (ADInstruments GmbH, Spechbach, Germany). All data were tested for normal distribution with the Kolmogorov-Smirnov test. Results were compared with pretreatment levels by repeated measures analysis of variance (ANOVA) and Bonferroni post hoc test.39 Results are given as mean percent change (%change) of the pretreatment level ± se except for the TFR. The latency between stimulation and tail-flick response (TFR-latency, tail-flick reflex latency [TFL]) were calculated as change in percent of the maximum possible effect (MPE%) according to Nadeson and Goodchild28: %MPE = 100 × ([TFLtreatment − TFLpretreatment] × [TFLoffset − TFLpretreatment]−1). The TFLoffset had been set at 15 s to avoid heating damage. Statistical analyses were performed using Prism4® software package for Macintosh (GraphPad Software, San Diego, CA).

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RESULTS

Effects of 8-OH-DPAT In Situ

All data were normally distributed. Baseline phrenic nerve frequency was 10.5 ± 1.6/min, and CFR amplitude 6.8 ± 0.5 mV with a latency of 41.0 ± 1.2 ms. Low doses of 8-OH-DPAT (0.001, 0.01 μM) had no effect on PNA but increased nociceptive responsiveness by increasing CFR amplitude (Fig. 2). The highest dose of 8-OH-DPAT (1 μM) significantly increased PNA to 74% ± 34% (Fig. 2A), whereas CFR amplitude returned to baseline (Fig. 2B). Subsequent 5-HT1A-R-antagonist WAY 100 635 (1 μM) antagonized 8-OH-DPAT and reduced PNA to the pretreatment level (−5.7% ± 19%, not illustrated). WAY 100 635 (n = 6), given alone, did not affect spontaneous PNA (1 μM, 3% ± 5%; 2 μM, 7% ± 16%; not shown); a tendency to depress CFR amplitude (1 μM, −18% ± 9%; 2 μM, −23% ± 17%; not shown) did not reach statistical significance.

Figure 2.

Figure 2.

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Interaction of 8-OH-DPAT with Fentanyl In Situ

Figure 3 shows a representative experiment on the counteraction of a fentanyl-induced depression of phrenic nerve minute activity by higher doses of 8-OH-DPAT in situ. Fentanyl markedly decreased PNA (Fig. 4) and nociceptive CFR amplitude (Table 1). Higher doses of 8-OH-DPAT significantly increased PNA (Fig. 4), whereas CFR remained depressed throughout experiments (Table 1). Completing experiments with naloxone (1 μM) returned CFR to −31% ± 12%, verifying integrity of the nociceptive reflex loop (data not shown). In the control group, fentanyl-induced depression of PNA and CFR (Table 1) persisted throughout NaCl 0.9% injections.

Figure 3.

Figure 3.

Figure 4.

Figure 4.

Table 1

Table 1

5-HT1A-R antagonist WAY 100 635 (1 μM), applied after fentanyl (1.4 ± 0.4 μM; n = 9), prevented subsequent 8-OH-DPAT (0.1 and 1 μM; n = 5) to counteract ventilatory depression. Both PNA and CFR remained depressed during application of 8-OH-DPAT and NaCl 0.9% (n = 4, data not shown).

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In Vivo Verification of Interaction of 8-OH-DPAT with Opioids

The respiratory rate in spontaneously breathing anesthetized rats was 53 ± 3/min, MAP 112 ± 3 mm Hg, and TFR latency 8 ± 1 s. Blood gas analyzes found pH 7.38 ± 0.03, Pco2 48 ± 3 mm Hg, and Po2 377 ± 61 mm Hg. All data were normally distributed, and baseline values of matched groups did not differ (Student’s t-test). 8-OH-DPAT dose dependently increased spontaneous MV, as in the in situ experiments (MV; 10 μg/kg: 47% ± 14%, P < 0.05, and 100 μg/kg: 43% ± 31%, P < 0.05, Table 2, upper panel). The effect on nociception was again dose dependent. The smallest dose of 8-OH-DPAT (0.1 μg/kg) significantly shortened TFR latency (−33% of MPE; P < 0.05, Table 2, lower panel), indicating an increased nociceptive responsiveness. On the contrary, the highest dose of 8-OH-DPAT (100 μg/kg) even abolished the TFR (100%MPE).

Table 2

Table 2

In the second in vivo series, 13 ± 2 mg/kg of morphine was required to depress MV to −86% ± 4% (P < 0.001) in the treatment group (Fig. 5) and to −81% ± 7% in the control group. Morphine consumption did not differ between groups. The arterial pH decreased to 7.24 ± 0.03, Po2 to 276 ± 65 mm Hg, and Pco2 increased to 71 ± 4 mm Hg. Similar to in situ, 8-OH-DPAT (10 μg/kg) increased spontaneous ventilation, prompting MV to return to −14% ± 19% of the pretreatment level (Fig. 5). The effects of the highest dose of 8-OH-DPAT (100 mg/kg) did not reach statistical significance.

Figure 5.

Figure 5.

The TFR was abolished in every experiment after the first morphine injection and remained depressed throughout 8-OH-DPAT administrations (Table 3). Naloxone-HCl in the end of experiments restored TFR with a latency of −11% ± 7% of MPE (not shown).

Table 3

Table 3

In the control group, MV and TFR remained depressed throughout NaCl 0.9% injections (Fig. 5). Because of a marked depression of MAP, no 8-OH-DPAT values larger than 100 μg/kg were obtained. In combination with morphine, circulatory depression was more pronounced, as two experiments failed to be completed because of circulatory collapse and pulmonary edema formation after the 100 μg/kg dose (Table 4).

Table 4

Table 4

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DISCUSSION

This study was performed to clarify whether stimulation of spontaneous breathing of 5-HT1A-R-agonist 8-OH-DPAT is associated with enhanced nociceptive responsiveness. We found both models of low concentrations of 8-OH-DPAT (0.001 and 0.01 nM in situ, 0.1 μg/kg in vivo) to enhance nociceptive reflexes. High concentrations (1 μM in situ, 10 μg/kg in vivo) stimulated spontaneous breathing, but did not enhance nociceptive responsiveness in situ, and even depressed nociception in vivo. Opioid suppression of nociceptive reflexes was not diminished in situ and in vivo.

In vivo, doses of 8-OH-DPAT higher than 10 μg/kg did not increase MV any further but rather provoked cardiovascular depression. In addition, in conjunction with morphine, fatal circulatory failure and pulmonary edema occurred in two animals. The highest dose was adopted from previous literature, in which no such complications were reported.19 8-OH-DPAT is not suitable for the use in humans, so investigations into other 5-HT1A-R-agonists will have to consider that the stimulation of spontaneous breathing might only be achieved with higher doses, in which cardiovascular depression and other specific serotonergic effects, such as nausea, vomiting, and serotonergic syndrome,40 may limit their applicability.

8-OH-DPAT (0.1, 1 μM in situ, and 10 μg/kg in vivo) sufficiently stimulated spontaneous breathing in opioid-induced ventilatory depression. As 5-HT1A-R-agonists were reported to both enhance and depress nociceptive reflexes,41–46 the second hypothesis of this study was that activation of 5-HT1A-R at a dose to stimulate spontaneous breathing does not diminish opioid-induced antinociception. We found small doses to activate nociceptive responsiveness and high doses to leave nociception unaffected in situ and even depress nociception in vivo. This dose dependency reconciles some of the published controversial findings22,25–29,47 and is in line with more recent work by Bardin et al.48 They reported a brief initial increase of nociception followed by a long-lasting antinociception upon single intraperitoneal administration of the novel 5-HT1A-R-agonist F 13640.

5-HT1A-R-antagonist WAY 100 635 completely antagonized activation of ventilation and prevented stimulatory effects of 8-OH-DPAT in fentanyl-induced ventilatory depression. This confirms that effects of 8-OH-DPAT on ventilation are predominantly attributable to 5-HT1A-R, which is in line with previous findings.20 It was not tested, however, whether WAY 100 635 would also antagonize small pronociceptive doses of 8-OH-DPAT, as it has been shown by others that WAY 100 635 completely prevented effects of 5-HT1A-R-agonist F13640 on nociception49 and did not display antinociception itself.26 Clarke et al.22 suggested the involvement of serotonin receptor subtypes other than 5-HT1A in the transmission of actions of 8-OH-DPAT on spinal reflexes. Because 8-OH-DPAT displays a weak affinity for 5-HT7-R at very high doses,50,51 the possible involvement of 5-HT7-R into nociception should be understood for future research.

Small doses of 8-OH-DPAT in combination with opioids in situ and in vivo did not enhance nociceptive responsiveness. They were most presumably over-powered by the potent antinociceptive opioids. Interestingly, when fentanyl was antagonized by naloxone in situ, CFR did not fully return to the pretreatment level, suggesting a sustaining antinociceptive effect by high dose 8-OH-DPAT. It is difficult to study the interaction of 5-HT1A-R-agonists and opioids simultaneously on spontaneous ventilation and nociception. This made us choose both a nonanesthetized in situ preparation and anesthetized rats with two different nociceptive models, as presented here. Although higher doses of 8-OH-DPAT were not associated with pronociceptive effects in both models, it should be noted that nociceptive modalities other than the two investigated here may be activated by low doses of 5-HT1A-R-agonists and may not be over-powered by opioids.

Most recently, the only available 5-HT1A-R-agonist approved for use in humans, buspirone, was reported not to counteract a morphine-induced ventilatory depression in healthy volunteers.52 Indeed, our group found buspirone, which is only a partial 5-HT1A-R-agonist, to be only a weak ventilatory stimulant in coadministration with fentanyl in the in situ PBSC preparation.53 Nevertheless, Oertel et al.52 concluded that a 5-HT1A-R-agonist other than buspirone might be a remedy against opioid-induced ventilatory depression.

The presented findings demonstrate that 5-HT1A-R-agonist 8-OH-DPAT activates spontaneous breathing without diminishing opioid-induced antinociception both in situ and in vivo anesthetized rats. Because of the eminent clinical significance of the findings presented here, further research should be directed toward 5-HT1A-R-agonists suitable for use in humans.

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ACKNOWLEDGMENTS

We thank Diethelm W. Richter for invaluable scientific support, Eike D. Schomburg and Heinz Steffens for meticulous technical advice during the establishment and verification of C-fiber reflex, and Tanja Schloesser for excellent assistance with in vivo experiments.

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