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Repinotan, a Selective 5-HT1A-R-Agonist, Antagonizes Morphine-Induced Ventilatory Depression in Anesthetized Rats

Guenther, U. MD*; Wrigge, H. PhD*; Theuerkauf, N. MD*; Boettcher, M. F. MD; Wensing, G. MD; Zinserling, J. PhD*; Putensen, C. PhD*; Hoeft, A. PhD*

doi: 10.1213/ANE.0b013e3181eac011
Anesthetic Pharmacology: Research Reports
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BACKGROUND: Spontaneous breathing during mechanical ventilation improves arterial oxygenation and cardiovascular function, but is depressed by opioids during critical care. Opioid-induced ventilatory depression was shown to be counteracted in anesthetized rats by serotonin(1A)-receptor (5-HT1A-R)-agonist 8-OH-DPAT, which cannot be applied to humans. Repinotan hydrochloride is a selective 5-HT1A-R-agonist already investigated in humans, but the effects on ventilation and nociception are unknown. In this study, we sought to establish (a) the effects of repinotan on spontaneous breathing and nociception, and (b) the interaction with the standard opiate morphine.

METHODS: The dose-dependent effects of repinotan, given alone or in combination with morphine, on spontaneous minute ventilation (MV) and nociceptive tail-flick reflex latencies (TFLs) were measured simultaneously in spontaneously breathing anesthetized rats. An additional series with NaCl 0.9% and the 5-HT1A-R-antagonist WAY 100 135 served as controls.

RESULTS: (a) Repinotan dose-dependently activated spontaneous breathing (MV, mean [95% confidence interval]; 53% [29%–77%]) of pretreatment level) and suppressed nociception (TLF, 91% maximum possible effect [68%–114%]) with higher doses of repinotan (2–200 μg/kg). On the contrary, nociception was enhanced with a small dose of repinotan (0.2 μg/kg; TFL, −47% maximum possible effect [−95% to 2%]). Effects were prevented by 5-HT1A-antagonist WAY 100 135. (B) Morphine-induced depression of ventilation (MV, −72% [−100% to −44%]) was reversed by repinotan (20 μg/kg), which returned spontaneous ventilation to pretreatment levels (MV, 18% [−40% to 77%]). The morphine-induced complete depression of nociception was sustained throughout repinotan and NaCl 0.9% administration. Despite a mild decrease in mean arterial blood pressure, there were no serious cardiovascular side effects from repinotan.

CONCLUSIONS: The 5-HT1A-R-agonist repinotan activates spontaneous breathing in anesthetized rats even in morphine-induced ventilatory depression. The potency of 5-HT1A-R-agonists to stimulate spontaneous breathing and their antinociceptive effects should be researched further.

Published ahead of print August 27, 2010 Supplemental Digital Content is available in the text.

From the *University Hospital of Bonn, Clinic of Anaesthesiology and Intensive Care Medicine, Bonn; and Department of Pharmacological Research, Bayer Schering Pharma AG, Wuppertal, Germany.

Supported by Bayer Schering Pharma AG, Germany, and departmental funding.

Address correspondence and reprint requests to Ulf Guenther, MD, University Hospital of Bonn, Clinic of Anaesthesiology and Intensive Care Medicine, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. Address e-mail to u.guenther@uni-bonn.de.

Accepted May 19, 2010

Published ahead of print August 27, 2010

Opioids are potent analgesics, but their clinical administration is limited by the intrinsic risk of fatal apnea. Hence, pain therapy involving opioids must be balanced against respiratory depression.1 The serotonin(1A)-receptor (5-HT1A-R)-agonist buspirone has been shown to stimulate spontaneous breathing in cats2 and to overcome neurogenic breathing disturbances in humans.3,4 Another 5-HT1A-R-agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a substance not approved for use in humans, has been demonstrated to overcome opioid-induced ventilatory depression in anesthetized rats.5

Nociception, another target of 5-HT1A-R-agonists, was reported either to be depressed68 or enhanced by 5-HT1A-R-agonists.9,10 Later, 5-HT1A-R-agonist F13640 was found to exert a dual effect, hyperalgesic and analgesic, depending on plasma and brain concentrations.11 Recently, enhancement of nociceptive reflexes by small doses of 8-OH-DPAT and suppression by higher doses were confirmed in 2 different experimental models.12

Repinotan (R-(−)-2-{4-[(chroman-2-ylmethyl)-amino]-butyl}-1,1-dioxobenzo[d]-isothiazolone hydrochloride) is a highly effective, selective, full 5-HT1A-R-agonist.13,14 Unlike other 5-HT1A-R-agonists, repinotan is approved for IV use in humans and has already undergone a series of clinical investigations into the effects of neuroprotection after traumatic brain injury and stroke.1518 However, its effects on nociception and ventilation are not yet established. The aim of this study was to verify the effects of repinotan on spontaneous breathing and nociception simultaneously, and to determine the interaction with the standard opiate morphine on spontaneous breathing and nociception in anesthetized rats. Two hypotheses were tested: (1) repinotan at a dose to stimulate spontaneous breathing does not enhance a nociceptive reflex, and (2) repinotan antagonizes morphine-induced depression of spontaneous breathing.

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METHODS

Animals

This study was performed with approval from the local Institutional Animal Review Board for animal research and in accordance with the “Guide for the Care and Use of Laboratory Animals.” Animals were housed in standard laboratory conditions with a 12-hour light/dark schedule and free access to food and water. Thirty-nine male Sprague-Dawley rats weighing 260 g (244–277 g) (mean, 95% confidence interval [CI]) were deeply anesthetized with sodium-pentobarbitone (60 mg/kg) intraperitoneally and placed supine on a heating pad to maintain rectal temperature constantly at 37°C ± 0.5°C. The right inguinal vessels were cannulated via a small surgical incision for continuous monitoring of arterial blood pressure and systemic administration of study drugs. Anesthesia was maintained with sevoflurane, leveled at an inspiratory concentration of 1.5 to 2.5 vol% to ensure immobility, stable spontaneous breathing, and detectable tail-flick reflex (TFR).

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Measurements

Animals breathed spontaneously via a tracheotomy tube (inner diameter, 1.2 mm). The expired air was led through the flowhead (order number, MLT1L; ADInstruments GmbH, Spechbach, Germany) of a spirometer (ML141) connected to an A/D-interface (PowerLab 4/25®; all devices from ADInstruments GmbH) to record respiratory rate (RR) and tidal volume (VT) by integration of ventilatory airflow over time. Minute ventilation (MV) was calculated as MV [mL/min] = RR [1/min] × VT [mL].

The TFR was evoked by a 100-W light beam source mounted 15 mm over the base of the tail to reach maximum temperature within a second. The latency of the reflex response (TFR latency, TFL) was recorded with a strain gauge attached to the tail distal to the heating spot. A shortened TFL indicates enhanced nociceptive responsiveness; an elongated TFL indicates depressed nociception. Heating was stopped when the tail flicked or after a maximum heating time of 15 seconds (TFLoffset) to prevent damage to the tail. TFLs were calculated as change in percent of the maximum possible effect [% MPE] according to the formula8: % MPE = 100 × [TFLtreatment − TFLpretreatment] × [TFLoffset − TFLpretreatment]−1). A 100% MPE means complete suppression of nociception. Three sweeps were recorded and averaged. A blood pressure transducer, temperature probe, and strain-gauge transducer were also connected to the same A/D-interface such as the spirometer (PowerLab 4/25®; ADInstruments GmbH).

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Drug Administration Protocols

Two different sets of experiments were performed: (a) the first set was aimed at determining the effects of repinotan on spontaneous breathing, and (b) the second set assessed interactions of repinotan with the opiate morphine (see Fig. 1 for schematic overview).

Figure 1

Figure 1

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Repinotan

Repinotan was injected IV every 15 minutes with doses ranging from 0.02 through 200 μg/kg (Fig. 1A). The doses were chosen because it was concluded from preliminary dose-finding experiments that the 20 μg/kg dose was the most efficient to counteract opioid-induced ventilatory depression. The wide range of dosage was necessary to verify whether repinotan also possesses dose-dependent pro- and antinociceptive effects similar to the standard 5-HT1A-R-agonist, 8-OH-DPAT. The number of experiments involving repinotan (n = 8) was chosen based on our previous experience with 8-OH-DPAT, in which the smallest effective dose increased spontaneous MV by 46% with a standard deviation of 35%. With an α set at 0.05, the power was calculated as 0.93 with n = 8 experiments in the double-sided power analysis.

Before the first drug administration, a series of 3 TFL sweeps was averaged and taken as the pretreatment level. Subsequent TFLs were taken 10 minutes after each drug administration. For control experiments, NaCl 0.9% was injected every 15 minutes instead of study drugs (n = 8). In another series of 4 experiments, the selective 5-HT1A-R-antagonist WAY 100 135 (1 mg/kg) was injected before administration of repinotan (n = 4).

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Repinotan/Morphine Coadministration

Morphine was injected at increments of 5 mg/kg until respiratory frequency was depressed to at least 50% of the pretreatment level. Thereafter, repinotan was added cumulatively at the same doses as in the first set (Fig. 1B). Control experiments were again performed by injection of 200 μL of NaCl 0.9% (n = 6). After completion of this series, the ventilatory dose-response curve had a bell shape. To delineate the top of the bell shape more precisely, 5 additional experiments were performed with repinotan concentrations that were between the initially intended measuring points (Fig. 1). To verify integrity of the TFR at the end of experiments, naloxone (1 mg/kg) was given (not shown).

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Statistical Analysis

All data were tested for normal distribution (Kolmogorov-Smirnov test). Pretreatment levels of matched groups were compared with the Student t test. All ventilatory variables were calculated as change in percent of pretreatment level (% change). Results of experiments without morphine were compared with the values before the first administration of study drugs (pretreatment level). Results of experiments involving morphine/repinotan coadministration were compared with the variables obtained after morphine administration. The results of the ventilatory experiments were analyzed by 1-way repeated-measures analysis of variance. Each repinotan concentration was compared with the pretreatment level (i.e., 0% change) by Dunnett multiple comparison post test.19 TFLs were calculated as change in % MPE as stated above and also analyzed by comparison of each drug concentration to pretreatment levels by Dunnett multiple comparison test. Data were processed with the Chart 4.0 and Scope 4.0 software package (ADInstruments GmbH); statistical analyses were performed using Prism4® software package for Macintosh (GraphPad Software Inc., San Diego, CA). Power analyses were done with the Simple Interactive Statistical Analysis (SISA) online software package (http://www.quantitativeskills.com/sisa/calculations/power.htm).

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Drugs

Repinotan was provided by the manufacturer, Bayer Healthcare AG (Wuppertal, Germany). Morphine-sulfate was purchased from Merck KG (Darmstadt, Germany), with permission from the German Institute for Pharmacy and Medical Products. WAY 100 135 was obtained from Tocris (Bristol, UK). Naloxone-HCl was purchased from Ratiopharm (Ulm, Germany). All compounds were diluted in isotonic saline at the respective concentrations; injection volumes were 200 μL.

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RESULTS

Effects of Repinotan

Spontaneous Ventilation

The mean pretreatment RR was 58 breaths/min (95% CI, 46–70 breaths/min) in the repinotan group versus 61 breaths/min (54–69 breaths/min) in the control group, and the mean arterial blood pressure (MAP) was 111 mm Hg (100–122 mm Hg) in the repinotan group versus 110 mm Hg (100–120 mm Hg) in the control group. The mean TFL was 7 seconds (5–9 seconds) in both groups. All data were normally distributed, and pretreatment values did not differ statistically. Repinotan dose dependently increased spontaneous MV (Fig. 2A), reaching the maximum effect (MV; 53% [29%–77%]) with the 200 μg/kg dose.

Figure 2

Figure 2

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Tail-Flick Reflex Latency

The repinotan effects on nociception were dose dependent: a small dose of repinotan (0.2 μg/kg) shortened TFL, whereas a high dose of repinotan (200 μg/kg) elongated TFL (Fig. 2B), meaning that nociception was enhanced with small doses and suppressed with higher doses.

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Controls

The 5-HT1A-antagonist WAY 100 135 (1 mg/kg, n = 4) did not significantly alter MV itself, but prevented repinotan from activating spontaneous MV (data not shown). Injections of NaCl 0.9% had neither detectable effects on ventilation nor nociception.

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Repinotan/Morphine Coadministration

Figure 3 shows a representative experiment on the antagonization of morphine-induced ventilatory depression, during which nociceptive TFR remains completely depressed by the sustained action of morphine. Morphine depressed spontaneous MV to −72% (−100% to −44%) and always abolished the TFR with the first dosing increment (Fig. 4). Morphine consumption did not differ between groups (Fig. 1).

Figure 3

Figure 3

Figure 4

Figure 4

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Spontaneous Breathing

Repinotan (after morphine) dose dependently activated spontaneous breathing (Fig. 4), resulting in a maximum MV of 18% (−40% to 77%) above the pretreatment level with the 20 μg/kg dose (P < 0.01, compared with morphine level). Further increases to doses >20 μg/kg returned MV to lower levels, giving the dose-response curve a bell shape.

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Nociception

TFR was abolished with the first bolus of morphine (TFL, 100% MPE), and remained completely suppressed throughout administrations of repinotan (n = 13) and control drugs (n = 6; P < 0.001, compared with pretreatment levels). Naloxone-HCl at the end of experiments verified the integrity of the TFR, because it returned with a TFL of 8% MPE (−18% to 33% MPE) (not shown).

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Cardiovascular Side Effects

Repinotan depressed MAP with higher doses (Table 1, n = 8), but this did not have deleterious effects on the experiments. Likewise, although morphine (12 mg/kg [8–16 mg/kg], n = 13) markedly depressed MAP, repinotan did not further aggravate arterial hypotension, and neither did NaCl 0.9% (Table 1). There were no serious cardiovascular complications.

Table 1

Table 1

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DISCUSSION

This study was performed to clarify whether the 5-HT1A-R-agonist repinotan also antagonizes opioid-induced ventilatory depression similar to other 5-HT1A-R-agonists. It was verified that (a) higher doses (2–200 μg/kg) of repinotan stimulated spontaneous breathing, small doses (0.2 μg/kg) enhanced nociception, and the highest dose (200 μg/kg) depressed nociception; and (b) morphine-induced depression of spontaneous breathing was antagonized by higher doses of repinotan, whereas depression of nociception persisted. Despite a mild depression of MAP, repinotan did not produce serious cardiovascular complications.

These findings confirm previous work in which the 5-HT1A-R-agonist 8-OH-DPAT was shown to antagonize an opioid-induced ventilatory depression without impairing antinociception.12 8-OH-DPAT, however, is not approved for human use. Buspirone, the only commercially available 5-HT1A-R-agonist for use in humans, has been shown to stabilize apneustic breathing disturbances.3 Buspirone, being only a partial 5-HT1A-R-agonist, failed to counteract a morphine-induced ventilatory depression in healthy volunteers,20 nor did it cause antinociceptive effects in healthy volunteers.21 In a direct comparison with 8-OH-DPAT, only a weak ventilatory stimulation in coadministration with fentanyl was found for buspirone in an in situ perfused brainstem–spinal cord preparation, whereas 8-OH-DPAT proved to be an effective ventilatory stimulant.22

Both enhancement and depression of nociception by 5-HT1A-R-agonists, given alone or in combination with opioids, have been variously reported.8,9,2326 More recently, the highly selective 5-HT1A-R-agonist F13640 was reported to induce both hyperalgesia and/or analgesia depending on the blood and brain concentration time course.11 Most notably, F13640 was also shown to alleviate opioid-induced hyperallodynia and neuropathic pain in rats.27,28 The dose-dependent pro- and antinociceptive effects of repinotan found in this study contribute to reconciling the past contradictory findings, which were at least in part attributable to different experimental models, drug administration routes, and dosing ranges.

The dose-response curve of 5-HT1A-R stimulation of spontaneous breathing after morphine-induced ventilatory depression is inversely U shaped or “bell shaped,” meaning that stimulatory effects subsided with high concentrations.29 Also, repinotan produced a combination of low-dose stimulation of the TFR followed by high-dose inhibition. This dose-response characteristic is generally referred to as “hormesis.”30 More than 30 receptor systems, including opioid and adrenergic receptors, were identified to have hormetic dose responses, and the serotonin (5-HT) receptor system is among them.31 The neuroprotective effects of 5-HT1A-R-agonists have been shown to have bell-shaped dose responses.32 It is proposed that the basic biological principle behind this is that a mild stress may promote function or action, and extreme stress may promote depressive or toxic action.30

Although hormesis can be observed in a wide range of receptor systems and agents, there is no one-for-all molecular mechanism. The 5-HT1A-R are variously located and involved at different levels in the modulation of opioidergic effects on nociceptive pathways.9,33 Activation of central 5-HT1A-R, for instance, has been shown to enhance opioidergic inhibition of spinal reflexes,33 whereas systemic (intraperitoneal, IV) administration of 5-HT1A-R-agonists produced both pro- and antinociceptive effects.7,11 Directly applied onto the spinal cord, activation of 5-HT1A-R inhibited nociceptive neural responses only with the highest studied dose of 8-OH-DPAT.8,34 We speculate that IV repinotan overpowered possible pronociceptive effects (mediated by spinal 5-HT1A-R) by actions via central 5-HT1A-R, once the administered dose was high enough to establish sufficient brain tissue concentrations. The underlying mechanisms of hormetic dose responses clearly deserve further research.30,35

The cardiovascular depression after repinotan administration was much less severe than that by 8-OH-DPAT. In previous work, we reported severe, occasionally fatal, cardiocirculatory depression with the highest dose of 8-OH-DPAT (100 μg/kg) in anesthetized rats.12 Others saw that 8-OH-DPAT prevented arterial hypotension induced by the short-acting opioid remifentanil in conscious, nonanesthetized rats.36 Unlike repinotan,13 8-OH-DPAT also stimulates 5-HT7-R,37 which are critical for activation of cardiac vagal input.38 For instance, blockade of central 5-HT7-R attenuates the bradycardia and pressor response to both chemoreflex activation (induced by intracisternal injection of potassium cyanide) and baroreflex activation (induced by IV phenylephrine).39 Activation of 5-HT7-R in turn might add to the depression of MAP seen in this study after morphine administration (Table 1), which was likely induced by peripheral vasodilation.40 Furthermore, it has been shown in anesthetized animals that the 5-HT1A- R-agonist F13640 markedly reduced the intraoperative requirement of the volatile anesthetic.36 The concentration of the anesthetic was maintained constant in this study according to our protocol, which certainly contributed to arterial hypotension caused by increasing PCO2 as the consequence of hypoventilation.

Some limitations of this study warrant comment. First, repinotan, a 5-HT1A-R-agonist, was developed as an antidepressant, and was also found to exert neuroprotective effects on in vivo rats.15 Despite promising clinical data in humans,16 multicenter studies failed to show favorable effects on neurological outcomes in patients with stroke and traumatic brain injury.17,18 Specific serotonergic complications of repinotan, such as headache, nausea and vomiting, flush, tachycardia, and agitation, in humans were reported.17,41 These symptoms may even be aggravated in coadministration with morphine.20 Specific serotonergic side effects were not seen in this study because of the experimental setup, but they could, however, limit the clinical applicability of repinotan at least in conscious patients.

Second, it should be highlighted that the morphine concentrations in this investigation were much higher than in studies aiming solely at nociception.42,43 This happened because morphine dosage was targeted to produce ventilatory depression, requiring higher dosing. The TFR was always abolished with the first bolus of morphine and always before ventilatory depression occurred. The possible attenuation of morphine-induced antinociception by small doses of repinotan was presumably overpowered by the strong morphine effect. We did not investigate to determine whether small pronociceptive doses of repinotan would interfere with more moderate doses of morphine. This should be considered for further research.

Third, the TFR is an acute, polysynaptic nociceptive spinal reflex.44 Although pronociceptive effects were seen only with very small doses of repinotan, but not within the dosing range to stimulate breathing, it is conceivable that small pronociceptive doses of repinotan could alleviate morphine antinociception. It was shown by others that 5-HT1A-R influence nociceptive processing differently, according to the type of noxious stimulus.45 Thus, nociceptive modalities other than the one investigated here may be activated by small doses of 5-HT1A-R-agonists, which may not be treated with opioids. This will be clarified by further investigations.

In conclusion, this work confirmed that the 5-HT1A-R-agonist repinotan activates spontaneous breathing and suppresses nociception with higher doses, and that it antagonizes morphine-induced ventilatory depression in anesthetized rats. Selective 5-HT1A-R-agonists thus are promising candidates for research into the stabilization of spontaneous breathing and pain therapy.

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AUTHOR CONTRIBUTIONS

UG, MFB, GW, HW, CP, and AH helped with study design; UG, NT, JZ, and GW helped with study conduction; UG, NT, and JZ helped with data collection; UG, NT, and JZ helped with data analysis; and UG, HW, MFB, NT, CP, and AH helped with manuscript preparation. All authors read and approved the final manuscript. UG and MFB reviewed the original study data and data analysis. UG maintains the study records.

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DISCLOSURE

Bayer Schering Pharma AG, Germany, provided the study drug and funded part of this study. MFB and GW are employees of Bayer Schering Pharma AG.

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