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Anesth Analg 2005;100:102-106
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000139355.86522.D1

ANESTHETIC PHARMACOLOGY

The Effect of Meperidine on Thermoregulation in Mice: Involvement of {alpha}2-Adrenoceptors

Andrea Paris, MD, Christina Ohlendorf, MD, Michael Marquardt, Berthold Bein, MD, James M. Sonner, MD*, Jens Scholz, MD, and Peter H. Tonner, MD

Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany; *Department of Anesthesia, University of California, San Francisco, California

Address correspondence to Andrea Paris, MD, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel Schwanenweg 21, D-24105 Kiel, Germany. Address e-mail to paris{at}anaesthesie.uni-kiel.de


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Meperidine has potent antishivering properties. The underlying mechanisms are not fully elucidated, but recent investigations suggest that {alpha}2-adrenoceptors are likely to be involved. We performed the current study to investigate the effects of meperidine on nonshivering thermogenesis in a model of thermoregulation in mice. After injection (0.1 mL/kg intraperitoneally) of saline, meperidine (20 mg/kg), the specific {alpha}2-adrenoceptor antagonist atipamezole (2 mg/kg), plus saline or atipamezole plus meperidine, respectively, mice were positioned in a Plexiglas chamber. Rectal temperature and mixed expired carbon dioxide were measured after provoking thermoregulatory effects by whole body cooling. Maximum response intensity of nonshivering thermogenesis and the thermoregulatory threshold for nonshivering thermogenesis, which was defined as the temperature at which a sustained increase in expiratory carbon dioxide can be measured, were investigated. Meperidine significantly decreased the threshold of nonshivering thermogenesis (36.6°C ± 0.7°C) versus saline (37.9°C ± 0.6°C) and versus atipamezole plus saline (37.8°C ± 0.4°C; P < 0.01). This effect was abolished after administration of meperidine combined with atipamezole (37.7°C ± 0.6°C; P < 0.05). Meperidine did not decrease the maximum intensity of nonshivering thermogenesis. The results suggest a major role of {alpha}2-adrenoceptors in the inhibition of thermoregulation by meperidine in mice.

IMPLICATIONS: Meperidine decreases the threshold for nonshivering thermogenesis in mice. This effect was abolished by administration of the {alpha}2-adrenoceptor antagonist atipamezole, suggesting a predominant role of {alpha}2-adrenoceptors in the inhibition of thermoregulation by meperidine. This model of thermoregulation in mice may be useful to further elucidate general mechanisms of thermoregulation.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Shivering is a common problem in patients recovering from anesthesia and is a major cause of discomfort. It is characterized by involuntary muscle activity that increases the metabolic rate (1). This may lead to dramatic increases of oxygen consumption and may trigger serious adverse events, especially in patients with cardiovascular disease (2,3). The underlying mechanisms of postanesthetic shivering are not fully understood, but the primary cause seems to be perioperative hypothermia caused by anesthetic-induced inhibition of thermoregulation (4,5).

Meperidine is more effective in treating shivering than equianalgesic doses of other opioids (6–9). The mechanisms of its special antishivering action are still under discussion and have been attributed, at least in part, to the action of meperidine on {kappa}-opioid receptors (10). In contrast, several investigations showed that meperidine is a potent agonist at {alpha}2-adrenoceptors at clinically relevant concentrations (11). Because {alpha}2-adrenoceptor agonists such as clonidine terminate and prevent shivering successfully and sometimes more potently than meperidine (12–14), we hypothesized that the antishivering action of meperidine is likely to be mediated by {alpha}2-adrenoceptors (11).

The study was designed to evaluate the effects of meperidine on thermoregulation in mice. Unlike humans, mice and other rodents use nonshivering thermogenesis as their primary defense against hypothermia (15,16). Therefore we used a model of nonshivering thermogenesis. To investigate the role of {alpha}2-adrenoceptors in mediating the action of meperidine on thermoregulation, we studied whether the specific {alpha}2-adrenoceptor antagonist atipamezole influences the effect of meperidine on thermoregulation in mice.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
After approval of the Institutional Animal Care and Use Committee, 10 male mice (129S2/SvHsd) weighing 28–40 g were investigated. Mice were housed 5 animals per cage and maintained on a 12-h light-dark cycle with free access to water and food. All experiments were conducted between 08:00 h and 16:00 h.

In a first set of experiments, animals received saline or meperidine (20 mg/kg), respectively. To investigate a possible role of {alpha}2-adrenoceptors in a second set of experiments, the {alpha}2-adrenoceptor antagonist atipamezole (2 mg/kg) was injected 30 min after the injection of saline/meperidine. All drugs were administered intraperitoneally (0.1 mL/10 g body weight), and animals were weighed on the day of experimentation for calculation. Each animal served as its own control and each mouse was studied with all four drug regimens (Group 1: saline, Group 2: meperidine, Group 3: saline plus atipamezole, and Group 4: meperidine plus atipamezole). Animals had at least 2 wk to recover from injections of atipamezole or meperidine before starting a new experiment.

The animals were returned to their cages after injection of saline (Group 1) or meperidine (Group 2), respectively, and stayed there until starting the measurement 60 min after injection. In a second set of experiments 30 min after injection of saline (Group 3) or meperidine (Group 4) mice were briefly removed from the cage for injection of atipamezole and immediately returned to the cage until start of measurement (Fig. 1). To prevent an inadvertent decline of body temperature, cages were warmed by a heating lamp. Sixty minutes after injection of meperidine (groups 2 and 4) or saline (groups 1 and 3), respectively, mice were positioned in a gas-tight Plexiglas chamber (internal diameter, 4 cm; length, 7 cm). A constant oxygen flow of 200 mL/min was delivered to the chamber. Mixed expired carbon dioxide was recorded continuously by capnography (Capnomac; Datex, Helsinki, Finland). Body temperature was measured by a rectal temperature probe (Exacon-Asmuth, Minden, Germany) and recorded continuously (Sirecust 402; Siemens, Danvers, MA). Ice was applied around the Plexiglas chamber to provoke a thermoregulatory response by whole body cooling. No animal was allowed to get colder than 32°C.



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  		Figure 1. Experimental design and data analysis: mixed expired carbon dioxide (•) and body temperature ({square}) as a function of time during whole body cooling. The thermoregulatory threshold temperature is defined as the first point at which a sustained increase in expiratory carbon dioxide can be measured after cooling. The maximum response intensity of nonshivering thermogenesis is the ratio of the maximum to the minimum carbon dioxide plateau (16).

 
According to studies in rats (16) the thermoregulatory threshold was defined as the temperature (°C) at which a sustained increase in expiratory carbon dioxide can be measured (Fig. 1). The maximum response intensity of nonshivering thermogenesis was calculated as the ratio of the maximum and minimum carbon dioxide plateau during cooling. To determine the thermoregulatory threshold, plots of mixed expired carbon dioxide (mm Hg) as a function of time were analyzed by three blinded observers and the median value of the three observers was taken for further analysis.

Data are presented as mean ± SD. Statistical significance was determined by using Student’s t-test for paired groups and P < 0.05 was considered significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The thermoregulatory threshold temperature was 37.9°C ± 0.6°C in mice receiving saline (Fig. 2). Additional administration of atipamezole did not change the threshold significantly (37.8°C ± 0.4°C). In contrast, meperidine caused a decrease in threshold of nonshivering thermogenesis to 36.6°C ± 0.7°C that was significant versus saline and versus atipamezole plus saline (P < 0.01). Addition of atipamezole to meperidine neutralized the effect of meperidine on the thermoregulatory threshold, which was restored to 37.7°C ± 0.6°C (P < 0.05 versus meperidine). This threshold was not significantly different from the threshold measured after injection of saline or atipamezole plus saline. Neither meperidine nor atipamezole influenced the maximum response intensity of nonshivering thermogenesis compared with saline (Fig. 3).



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  		Figure 2. Thermoregulatory threshold temperature in mice after injection of saline, meperidine, atipamezole plus saline, and atipamezole plus meperidine (n = 10 per group). Data are presented as mean ± SD. #P < 0.01 versus saline and versus saline plus atipamezole; §P < 0.05 versus meperidine plus atipamezole.

 


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  		Figure 3. Maximum response intensity of nonshivering thermogenesis in mice after injection of saline, meperidine, atipamezole plus saline, and atipamezole plus meperidine (n = 10 per group). Data are presented as mean ± SD.

 
Baseline temperatures were similar in all four groups. However, rectal temperature in mice receiving meperidine alone tended to decrease when these animals were exposed to room temperature. To maintain normothermia until starting whole body cooling we had to increase the ambient temperature by warming the cage with a heating lamp. To provide stable experimental settings warming was performed in all groups. However, after starting whole body cooling in mice receiving meperidine alone, body temperature tended to decline faster and decreased to the cutoff value of 32°C in 4 animals. This was not observed with any other drug regimen during the study period. No signs of shivering or piloerection were observed at this temperature.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The present results show that meperidine decreases the thermoregulatory threshold temperature for nonshivering thermogenesis in mice. The specific {alpha}2-adrenoceptor antagonist, atipamezole, has no influence on thermoregulation, but it diminishes the inhibition of thermoregulation induced by meperidine in mice. Atipamezole is an {alpha}2-adrenoceptor antagonist that has a high {alpha}2/{alpha}1-selectivity ratio and does not display differential affinity for {alpha}2-adrenoceptor subtypes (17). It is well tolerated over a wide dosage range and widely used in veterinary medicine. The dosage used in this study proved to reverse {alpha}2-mediated effects in mice (18). Studies on its pharmacology showed that atipamezole has no marked effects on systems other than {alpha}2-adrenoceptors and therefore can be viewed as a specific pharmacological tool suitable for evaluating effects on {alpha}2-adrenoceptors in vivo (17).

The exact mechanisms of the antishivering activity of meperidine remain to be shown. Meperidine treats shivering far better than equianalgesic doses of other more specific µ-opioids (6–9). This pronounced antishivering efficacy was attributed to an interaction with {kappa}-receptors (10). However, even very large doses of naloxone, blocking µ- and {kappa}–receptors, did not completely abolish the antishivering action of meperidine in volunteers (10). It can be speculated that the remaining antishivering activity is attributable to an incomplete blockade of {kappa}-receptors or to an effect of meperidine on non-opioid receptors. Moreover, pentazocine, a more specific {kappa}-agonist than meperidine, was not effective in the treatment of shivering in humans (6). Like meperidine, {alpha}2-adrenoceptor agonists such as clonidine terminate and prevent shivering successfully and the effect is even more pronounced (12–14). Takada et al. (11) demonstrated that meperidine is a potent agonist at {alpha}2B-adrenoceptors at clinically relevant concentrations, indicating that the antishivering activity of meperidine may be mediated by {alpha}2B-adrenoceptors (11). This is supported by the findings of Doufas et al. (19) who showed in volunteers that meperidine and the {alpha}2-adrenoceptor agonist dexmedetomidine additively reduce the shivering threshold, thus providing indirect support for the theory that the special antishivering effect of meperidine is mediated by its central {alpha}2-adrenoceptor activity. This is consistent with the results of our study. Atipamezole, a specific {alpha}2-adrenoceptor antagonist, abolishes the effect of meperidine on nonshivering thermogenesis in mice. The thermoregulatory threshold temperatures between meperidine plus atipamezole and saline, with or without atipamezole, are similar. In contrast, meperidine alone leads to a significant reduction in thermoregulatory threshold temperature versus saline as well as saline plus atipamezole and meperidine plus atipamezole.

There are some limitations to our study. We investigated a relatively small number of animals, leading to a certain variability in our experimental results. Small differences between meperidine plus atipamezole and saline or saline plus atipamezole may not have been detected because of the small sample size. Therefore, it cannot be concluded that the effects of meperidine on thermoregulation in mice are exclusively mediated by {alpha}2-adrenoceptors. In fact, previous studies in volunteers showed that alfentanil, a pure µ-receptor agonist, decreases the shivering threshold, thus clearly documenting involvement of µ-receptors in thermoregulation (20,21). Meperidine causes a variety of effects. Besides interactions with opioid receptors and {alpha}2-adrenoceptors, local anesthetic properties (22,23) and a central anticholinergic action (24,25) are well documented. Correspondingly, multiple pathways, such as adrenergic (26–28), cholinergic (13), and serotonergic (14,29,30) systems, seem to be involved in thermoregulation. The redundancy of pathways involved in thermoregulation possibly reflects the importance of thermoregulation in homeothermic species. Thus, it can be speculated that the effect of meperidine on thermoregulation in mice is primarily mediated by {alpha}2-adrenoceptors in mice, but other pathways can also be involved. A combined effect on more than one pathway may explain the pronounced antishivering efficacy in humans.

According to studies in volunteers (21), meperidine does not decrease the maximum response intensity of nonshivering thermogenesis. This is consistent with the results of the present study and supports the conclusion that the special antishivering effect of meperidine is primarily mediated by a reduction of the shivering threshold and does not result from reducing the maximum shivering intensity (21).

Data from animals should be extrapolated to humans with caution. Human adults use thermoregulatory vasoconstriction and shivering as defenses against hypothermia whereas nonshivering thermogenesis contributes little to thermoregulation (1). Unlike in adult humans, nonshivering thermogenesis is the primary thermoregulatory defense in rodents (1,16).

Thermoregulation is far better evaluated in humans than in animals. However, previous studies showed that anesthetics and opioids inhibit thermoregulation in rodents as well as in humans (16,31,32). The effects of opioids on thermoregulation in animals are to some extent species-specific. Small doses of various µ-agonists produce hyperthermia, whereas large doses produce hypothermia in mice (32). This is consistent with the findings of the present study using large doses of meperidine. After administration of meperidine, core temperature tends to decline in mice exposed to room temperature for a longer period of time. To maintain normothermia we had to increase the ambient temperature by warming the cage, which was done with all drug regimens to ensure constant experimental conditions and allow for comparison of the results. This management resulted in similar baseline temperatures with all groups.

An additional limitation to this study is that the experiments were not conducted in a blinded fashion because mice exposed to meperidine were mildly sedated. To compensate for this effect, plots of mixed expired carbon dioxide versus time were analyzed by three blinded observers and the thermoregulatory threshold temperature was taken as the median value of the three observers.

In summary, the present results indicate that meperidine decreases the threshold for nonshivering thermogenesis in mice. This effect was abolished by the specific {alpha}2-adrenoceptor antagonist atipamezole, suggesting a predominant role of {alpha}2-adrenoceptors in the inhibition of thermoregulation by meperidine in mice.


   Footnotes
 
Presented, in part, at the Annual Meeting of the American Society of Anesthesiologists.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication June 24, 2004.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press