Questioning the cardiocirculatory excitatory effects of opioids under volatile anaesthesia

M.-A. Docquier, P. Lavand'homme, V. Boulanger, V. Collet and M. De Kock*

Department of Anaesthesiology, Laboratory of Anaesthesia, University of Louvain, St Luc Hospital, av. Hippocrate 10–1821, 1200 Brussels, Belgium

* Corresponding author. E-mail: dekock{at}anes.ucl.ac.be

Accepted for publication April 29, 2004.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. Opioid-induced hyperalgesia has been demonstrated in awake animals. We observed an increased haemodynamic reactivity in response to noxious stimuli in rats under sevoflurane anaesthesia treated with a very low dose of sufentanil. The aim of this investigation was to determine whether the two phenomena share a common origin: an opioid-induced excitatory reaction. To address this, we administered several drugs with proven efficacy in opioid hyperalgesia to rats presenting with haemodynamic hyper-reactivity.

Methods. The MACbar of sevoflurane was measured in controls and in animals treated with sufentanil 0.005 µg kg–1 min–1 before and after administration of i.v. (0.25, 0.5 mg kg–1) and intrathecal (i.t.) (250 µg) ketamine, i.v. (0.5, 1 mg kg–1) and i.t. (30 µg) MK-801(NMDA antagonist), i.v. (0.1, 0.5 mg kg–1) naloxone, i.v. (10 mg kg–1) and i.t. (50, 100 µg) ketorolac or i.t. (100, 150 µg) meloxicam (COX-2 inhibitor).

Results. Sufentanil 0.005 µg kg–1 min–1 significantly increased MACbar (3.2 (SD 0.3) versus 1.9 (0.3) vol%). With the exception of naloxone, all drugs displayed a significant MACbar-sparing effect (>50%) in controls. Naloxone completely prevented haemodynamic hyperactivity. Two patterns of reaction were recorded for the other drugs: either hyper-reactivity was suppressed and the MACbar-sparing effect was maintained (i.t. ketamine, i.t. MK-801, i.t. ketorolac [100 µg], i.t. meloxicam [150 µg]) or hyper-reactivity was blocked but MACbar-sparing effect was lost (i.v. ketamine [0.5 mg kg–1], i.v. MK-801 [0.5, 1 mg kg–1], i.v. ketorolac [10 µg kg–1], i.t. ketorolac [50 µg], i.t. meloxicam [100 µg]).

Conclusions. We have demonstrated that low-dose sufentanil-induced haemodynamic hyper-reactivity is an excitatory µ-opiate-related phenomenon. This effect is reversed by drugs effective in treating opiate-induced hyperalgesia.

Keywords: anaesthetics volatile, sevoflurane ; analgesics opioid, sufentanil ; pain, mechanisms


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In a previous study designed to evaluate the MAC-sparing effect as ‘an objective tool’ to assess antinociception in animals we demonstrated that a very low dose of the µ opiate agonist sufentanil paradoxically increased the MACbar of sevoflurane.1 We speculated that this phenomenon is an excitatory opiate-induced effect revealed by the administration of sevoflurane. Recently, much attention has been paid to these opiate-induced excitatory effects. It appears that, although opiates are undoubtedly the most potent and useful analgesics for alleviating pain in humans, these substances concomitantly induce both inhibitory and excitatory effects.2 3

Using a pharmacological approach, the present investigation intends to determine the similarities, if any, between this opiate-induced excitatory haemodynamic phenomenon unmasked by sevoflurane and the hyperalgesia consecutive to opiate administration that was observed in awake animals.4 For this purpose, several drugs known to interfere with opiate acute tolerance37 were tested to reverse this opiate-induced haemodynamic hyper-reactivity. They include the NMDA antagonists ketamine and MK801, the opiate antagonist naloxone and Cox-1, and the Cox-2 inhibitors ketorolac and meloxicam.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Adult male Wistar rats (Janvier, France) weighing 300–400 g were used for all experiments. Rats were maintained on a 12:12 h light–dark cycle and received food and water ad libitum. After institutional animal care committee approval, the effects of the different drugs on the opiate-induced haemodynamic hyper-reactivity consecutive to noxious stimuli in sevoflurane anaesthetized rats were recorded.

Animals designed to receive intrathecal (i.t.) medications were implanted with chronic lumbar intrathecal catheters as described by Yaksh and Rudy.8 Briefly, rats were anaesthetized with sevoflurane and an intrathecal catheter (PE-10 tubing) was inserted through a small hole in the cisterna magnum and advanced 8 cm caudally such that the tip lay in the intrathecal space around the lumbar enlargement. The animals were allowed to recover over a period of 4–5 days. Rats showing neurological deficit were immediately killed by an overdose of pentobarbital. Then the correct placement of the spinal catheter was assessed by injection of lidocaine 500 µg. Animals that did not display complete motor blockade were excluded. During the study, the tests were performed between 10 a.m. and 4 p.m.

Determination of MACbarsevo (minimum alveolar concentration of sevoflurane that blocks cardiovascular response to noxious stimulus)
Sevoflurane was obtained from Abbott Laboratories (Chicago, USA). The methodology was comparable to the one used in previous work.1 Briefly, rats were placed in an induction chamber to which sevoflurane 8% in a continuous oxygen flow of 3 litre min–1 was directed (Sevoflurane Vaporizer; Dräger, Lübeck, Germany). After 2–3 min, the inspired sevoflurane concentration was reduced to 3%. After approximately 5 min, the animals were removed from the induction chamber and positioned supine. Sevoflurane was administered via a plastic cone.

Tracheotomy was performed and a 16 gauge polyethylene catheter inserted. The correct position of the catheter was checked before it was connected to a small T-piece (minimal dead space). Fresh gas flow to the T-piece was adjusted to 1 litre min–1, and sevoflurane concentration was adjusted as required by prevailing conditions. The femoral artery and vein of one hindpaw were catheterized with a fine tubing (PE-50) via surgical cutdown.

Monitoring. At the end of this surgical preparation, mechanical ventilation (modified Spiromat 650 ventilator; Dräger, Lübeck, Germany) was started with oxygen (, 100%; Vt, ±10 ml kg–1; respiratory rate, 35–45 bpm). Ventilation was adjusted for an end-tidal CO2 of approximately 25–30 mmHg (Datex, AS3, Helsinki, Finland) and a maximum peak pressure of 25 mmHg. Arterial blood pressure via the femoral catheter connected to a pressure transducer (Edwards Lifesciences, Unterschleissheim, Germany) and electrocardiogram were continuously monitored (Datex, AS3, Helsinki, Finland). Arterial blood gases were measured at the end of the experiment to ensure that the values were within normal limits of pH (7.35–7.45), oxygen pressure (>90 mmHg) and carbon dioxide pressure (30–40 mmHg). Rectal temperature was monitored and maintained between 37 and 38°C by means of heating light.

Determination of minimum alveolar concentration. Inspiratory and end-expiratory sevoflurane concentrations were continuously measured by an IR spectrometer (Datex AS3 Helsinki, Finland), calibrated before each manipulation. Samples were collected at the tip of the endotracheal canula (0.5 cm above the carina).

After every step change in anaesthetic concentration delivered by the anaesthetic circuit, an equilibration time (inspiratory sevoflurane concentration equal to end expiratory) was allowed (at least 15 min) before a new noxious stimulus was applied.

The value of the minimum alveolar concentration of sevoflurane that blocks cardiovascular response to noxious stimulus (MACbarsevo) was established according to the method described by Eger and colleagues9 and Roizen and colleagues.10 A noxious stimulus was applied with a long haemostat (8-inch Rochester Dean Hemostatic Forceps; Martin, Tuttlingen, Germany) clamped to the first ratchet lock on the tail for 30 s. The tail was always stimulated proximal to a previous test site. A 10% increase in systolic arterial blood pressure was considered a positive response. No change or a change below this threshold was considered a negative response. In all cases, measurements were started at equilibrium with 1.5 vol% sevoflurane. According to the cardiovascular response, the sevoflurane concentration was then adjusted in decrements or increments of 0.2% until the negative response became positive or the positive response became negative.

All measurements were performed in apnoea to avoid haemodynamic variations related to the different phases of mechanical ventilation.

Experimental design. Basal (predrug) MACbarsevo was determined in every animal. Rats then received drugs known to interfere with acute opiate tolerance (ketamine, MK801, naloxone, ketorolac, meloxicam) or saline 15 min after the predrug MACbarsevo measurement. A second MAC determination followed, and 15 min later the excitatory dose of sufentanil (Janssen Pharmaceutica, Beerse, Belgium) was administered. The excitatory dose of sufentanil, as assessed by a previous investigation,1 consisted of a bolus of 0.015 µg kg–1 followed by a continuous infusion of 0.005 µg kg–1 min–1. After predrug (control group) MACbar assessment, the animals were randomly assigned to receive one of the following drugs: i.v. ketamine (0.25, 0.5 mg kg–1), i.t. ketamine (250 µg), i.v. MK-801 (0.5, 1 mg kg–1), i.t. MK-801 (30 µg) (dose chosen according to Ishizaki and colleagues11), i.v. naloxone (0.1, 0.5 mg kg–1), i.v. ketorolac 10 mg kg–1, i.t. ketorolac (50, 100 µg) or i.t. meloxicam (100, 150 µg) (Boerhinger Ingelheim, Ingelheim, Germany). Six animals were studied for each condition. MACbarsevo determination in treated animals was carried out 30 min after the previous evaluation (predug) and was performed according to the same method.

Only rats with a normal systolic arterial blood pressure (110–160 mmHg) after initial instrumentation were included. During the study protocol, animals presenting with persistent low systolic arterial blood pressure (<100 mmHg not responding to 2 ml Haemacel fluid supplementation) were excluded from data analysis.

Statistical analysis
MACbarsevo for each rat was calculated as follows. During each experiment, the first change in reaction (i.e. from reaction to pain stimulus to no reaction) was registered and the mean of the two adjacent doses of sevoflurane (i.e. immediately before and immediately after the change) was taken as the MACbarsevo. The normal distribution of the data was assessed by the Kolmogorov–Smirnov test. Different MAC values were compared using repeated measures of analysis of variance, followed by post hoc analysis using Tukey's test. The same tests were applied for intra- and intergroup comparison of the change in systolic arterial blood pressure.

Results are presented as mean (SD), and P<0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Two animals presenting with profound hypotension after initial instrumentation were excluded. Consequently, two animals were added to maintain the initial group size of six. The average MACbarsevo value (predrug MACbarsevo) before treatment was 1.9 (SD 0.3) vol%. Administration of i.v. sufentanil 0.005 µg kg–1 min–1 to saline controls significantly increased this value to 3.2 (0.3) vol% (P<0.05).

Effects of drugs on MACbarsevo (Figs 1, 2 and 3)
With the exception of naloxone, all drugs reduced the predrug MACbarsevo. Both i.v. ketamine 0.5 mg kg–1 and i.t. ketamine reduced MACbarsevo by approximately 70%. Intravenous MK-801 1 mg kg–1 and i.t. MK-801 30 µg reduced MACbarsevo by approximately 40% and 76%, respectively. Of the COX inhibitors, i.t. meloxicam 150 µg was the most efficacious with a 90% reduction.



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Fig 1 MACbar sevoflurane (vol%) in animals (six per condition) treated with i.v. ketamine (K) (0.25, 0.5 mg kg–1), i.t. ketamine (250 µg), i.v. MK-801 (0.5, 1 mg kg–1), i.t. MK-801 (30 µg) without and with sufentanil 0.005 µg kg–1 min–1. MACbar sevoflurane and MACbar sevoflurane+sufentanil 0.005 µg kg–1 min–1 in saline-treated animals (means+SD) are presented in the horizontal boxes. *Significantly different (P<0.05) from saline control animals. +Significantly different (P<0.05) from saline–sufentanil-treated animals. ++Significantly different (P<0.05) from saline control and saline–sufentanil-treated animals.

 


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Fig 2 MACbar sevoflurane (vol%) in animals (six per condition) treated with i.v. naloxone (N) (0.1, 0.5 mg kg–1) without and with sufentanil 0.005 µg kg–1 min–1. MACbar sevoflurane and MACbar sevoflurane+sufentanil 0.005 µg kg–1 min–1 in saline-treated animals (means+SD) are presented in the horizontal boxes. +Significantly different (P<0.05) from saline–sufentanil-treated animals.

 


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Fig 3 MACbar sevoflurane (vol%) in animals (6 per condition) treated with i.v. ketorolac (Ke) 10 mg kg–1, i.t. ketorolac (50, 100 µg) or i.t. meloxicam (M) (100, 150 µg) without and with sufentanil 0.005 µg kg–1 min–1. MACbar sevoflurane and MACbar sevoflurane+sufentanil 0.005 µg kg–1 min–1 in saline-treated animals (means+SD) are presented in the horizontal boxes. *Significantly different (P<0.05) from saline control animals. +Significantly different (P<0.05) from saline–sufentanil-treated animals. ++Significantly different (P<0.05) from saline control and saline–sufentanil-treated animals.

 
Effects of drugs on sufentanil-induced cardiocirculatory hyperexcitability (Figs 1, 2 and 3)
When considering the effects of the agents that significantly reduced MACbarsevo, two patterns are observed on the excitatory effect of sufentanil. With i.t. ketamine, MK-801 (Fig. 1), ketorolac 100 µg and meloxicam 150 µg (Fig. 2), MACbar was lower than during sevoflurane without sufentanil in control animals (sevoflurane without sufentanil) as well as in sufentanil-treated control animals (sevoflurane+sufentanil). In contrast, with i.v. ketamine (0.5 mg kg–1), MK-801 (Fig. 1) and ketorolac (Fig. 2), while MACbar was also lower than during sevoflurane without sufentanil in control animals (sevoflurane without sufentanil), in the sufentanil-treated animals MACbar was lower than during sevoflurane+sufentanil and comparable to, but not lower than, MACbar during sevoflurane without sufentanil.

Intravenous naloxone 0.5 mg kg–1 completely prevented the sufentanil-induced increase in MACbarsevo.

None of the drugs significantly affected systolic arterial pressure.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Our results show that both non-specific and specific antagonists at NMDA receptors, ketamine and MK-801 prevent the sufentanil-induced increase in cardiocirculatory reactivity in response to a noxious stimulus in animals under sevoflurane anaesthesia. This inhibitory effect is particularly evident when these drugs are administered spinally. The opiate receptor antagonist naloxone completely suppressed sufentanil-induced increase in MACbar. Concerning the mechanisms involved, our pharmacological challenge supports an excitatory reaction occurring at the spinal level initiated by the opioid receptor and mediated by the NMDA receptor. This is in accordance with recent theory of the biphasic effects of opioids on nociceptive perception.2 3 According to this theory, opioids concomitantly induce both inhibitory effects (i.e. antinociceptive effects) and excitatory effects (i.e. pronociceptive, hypersensitivity or hyperalgesic effects, pruritus and nausea). The cardiocirculatory hyperactivity following noxious stimulation appears to be another opioid-induced excitatory manifestation revealed by the experimental setting used.

Non-competitive antagonists at the N-methyl-D-aspartate receptor, ketamine and MK-801 were used because the excitatory neurotransmitter glutamate plays a pivotal role in the development and maintenance of opioid-induced excitatory effects via these receptors.12 For example, ketamine has been demonstrated to prevent opioid hyperalgesia in animals and humans.35 13 In our study, the selective NMDA antagonist MK-801 was used in order to determine that the effect observed after ketamine administration is related to antagonism at the NMDA receptor. This was done because ketamine can act on several receptor systems, such as the opioidergic (µ, {delta}, {kappa})14 15 and cholinergic (muscarinic and nicotinic)15 systems, involves the monoaminergic system16 and shows local anaesthetic effects by blockade of the sodium channels.17 Concerning the routes of administration (i.v. versus i.t.), it is interesting to point out that whereas i.v. ketamine and MK-801 both reverse sufentanil-induced increase in MACbarsevo, their ‘specific’ sevoflurane MACbar-sparing effect is lost. In contrast, i.t. ketamine and MK-801 inhibit the exacerbated haemodynamic reactivity but maintain their sevoflurane MACbar-sparing effect. This finding argues in favour of a preferential spinal site for MACbar. These data are in agreement with a previous study where we demonstrated a spinal site of action for the MACbar-sparing effect of i.v. clonidine.18 It also highlights the important role played by spinal NMDA receptors in the processing of spinal polysynaptic reflexes,19 and particularly of cardiocirculatory responses following noxious stimulation as already assessed for pain perception (wind-up phenomenon).20 21

Low doses (0.5 mg kg–1) of the specific opioid antagonist naloxone are devoid of effect on the MACbarsevo whereas it totally prevents the sufentanil-induced increase in this response. Hence the recorded excitatory manifestation is mediated by opiate receptors. This observation is consistent with the work of Crain and Shen.2 Using a multidisciplinary approach based on nociceptive neurones in culture, behavioural assays in mice and clinical trials on post-surgical pain patients, these authors demonstrated a specific effect of low doses of naloxone or nalmefene on Gs-coupled excitatory opioid receptor functions together with markedly enhanced morphine antinociceptive potency and simultaneous attenuation of opioid tolerance and dependence by co-treatment with these opioid antagonists.

The results obtained with non-steroidal anti-inflammatory drugs (NSAIDs) are of particular interest. Ketorolac, the non-specific COX-1/COX-2 inhibitor, and meloxicam, the more selective COX-2 inhibitor, significantly reduced MACbarsevo in control and sufentanil-treated animals. Such an observation is not surprising. While it is clear that NSAIDs exert their analgesic effect by interacting with local inflammatory processes, strong evidence also exists for a central analgesic effect22 23 or, rather, an anti-hyperalgesic effect as previously demonstrated in animal models.24 25 Spinal administration of NSAIDs provides efficient analgesia in humans26 and an intraoperative anaesthetic-sparing effect of systemic NSAIDs has been described in surgical patients.27 A spinal interaction between cyclooxygenase and NMDA receptor activity seems to partly account for this central effect of NSAIDs7 which may explain the positive results we observed in our model on sufentanil-induced haemodynamic hyper-reactivity. It has been demonstrated that COX-2 expressed in the central nervous system colocalizes with glutamate in excitatory neurones and that NMDA receptor activation results in increased prostanoid synthesis.28

In conclusion, using a pharmacological approach, we were able to confirm the similarity between opiate-induced hyperalgesia in awake animals and an increased cardiocirculatory reactivity following a noxious stimulus in rodents under sevoflurane anaesthesia and low-dose opioid. Does the present study indicate that sevoflurane exacerbates the excitatory effects of the opiates? From a theoretical point of view, this appears unlikely because volatile anaesthetics inhibit rather than stimulate NMDA-mediated excitatory neurotransmission.29 It appears that sevoflurane exacerbates both excitatory and inhibitory effects of opiates on nociception because, in our previous study with this model,1 we observed significant MAC-sparing effects using doses of sufentanil that were completely ineffective in awake animals.


    Acknowledgments
 
The authors wish to thank Geert Byttebier M.Sc. for the statistical analysis and Dr C Craddock-de Burbure for revising the manuscript. This work was exclusively supported by the Department of Anaesthesiology of the University of Louvain, St. Luc Hospital.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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