POSTANESTHETIC shivering is characterized by involuntary muscle activity, especially during the early postoperative period, and can be treated pharmacologically with opioids or α2
-adrenoceptor agonists. Though the underlying mechanisms of shivering are not completely understood, a major contributing factor is perioperative hypothermia mediated by anesthetic-induced inhibition of thermoregulation.1,2
Previous studies have revealed that meperidine seems to be more effective in treatment of shivering than equianalgesic doses of other opioids, especially μ-opioid agonists.3
Possibly, meperidine’s ability to also stimulate κ-opioid receptors may contribute to this effect.4
However, meperidine is known to also initiate nonopioid receptor–mediated effects in clinically relevant concentrations, e.g.
, activation of α2
On the other hand, α2
-adrenoceptor agonists such as clonidine or dexmedetomidine proved to be even more effective in treatment of postanesthetic shivering than meperidine.6,7
Laboratory investigations in mice confirmed a pivotal role of α2
-adrenoceptors in thermoregulation and have revealed the α2A
-adrenoceptor as primary mediator of hypothermic effects of α2
Therefore, the aim of our study was to analyze the effect of meperidine on α2
-adrenoceptor–mediated thermoregulation in mice. Because rodents try to resist hypothermia by nonshivering thermogenesis, we focused on a mouse model of nonshivering thermogenesis that has been used by our group before.10
These experiments have revealed that meperidine mediates thermoregulatory effects via
-adrenoceptors but did not investigate any α2
-adrenoceptor subtype specifically. To evaluate the individual role of each of the three α2
-adrenoceptor subtypes, we compared impact of meperidine using wild-type mice and mice with deletion of the α2A
-, or α2C
-adrenoceptor (knock-out mice). To differentiate between opioid receptor and α2
-adrenoceptor–mediated effects, we also studied meperidine effects following administration of the opioid receptor antagonist naloxone and the α2
-adrenoceptor antagonist atipamezole.
Materials and Methods
Permission for this study was received from the local Animal Care Committee at the Ministry for Agriculture and Environment, Kiel, Germany, before the initiation of work. The generation of mouse lines lacking a single α2
-, or α2C
-adrenoceptor knock out) has been described previously.11,12
The knock-out mice were obtained from L. Hein (Freiburg, Germany), and maintained in a specified pathogen-free facility at our institution where all experiments were performed. Also, wild-type mice (129S2/SvHsd) were analyzed as a control group.
Ten mice of each group weighing 26–35 g were investigated. Mice were housed 3–4 animals per cage and maintained on a 12-h light-dark cycle with free access to water and food. All experiments were performed between 09:00 and 16:00 h. The animals were weighed before the experiments. In a first set of experiments, animals received saline or meperidine (20 mg/kg) (Dolantin; Sanofi-Aventis, Frankfurt, Germany), respectively. To rule out that a possible effect of meperidine is mediated via opioid receptors, in a second set of experiments, the opioid receptor antagonist naloxone hydrochloride (125 μg/kg) (Naloxon Curamed; Curamed Pharma, Karlsruhe, Germany) and the α2-adrenoceptor antagonist atipamezole (2 mg/kg) were injected 20 min after the injection of saline/meperidine.
To investigate possible effects of different opioids on the thermoregulatory threshold temperature that can be reversed by naloxone, we also analyzed fentanyl (50 μg/kg) (Fentanyl-Janssen; Janssen-Cilag, Neuss, Germany) plus naloxone (125 μg/kg) as an additional control.
To rule out that 125 μg/kg naloxone was not sufficient to completely reverse opioid receptor–mediated effects, a control group of 10 α2C-adrenoceptor knock-out mice received meperidine plus different naloxone doses (125 vs. 1250 μg/kg). All drugs were administered intraperitoneally (0.1 ml/10 g body weight).
Each animal was analyzed with all six different drug regimens (saline, meperidine, saline plus naloxone, meperidine plus naloxone, fentanyl plus naloxone, and meperidine plus atipamezole) and therefore served as its own control. Before a new experiment was started, animals had at least 2 weeks to recover from injections of pharmaceuticals. After injection of saline or meperidine, the animals were returned to their cages until starting the measurements 40 min later. In a second set of experiments, 20 min after injection of saline (for saline plus naloxone experiment), meperidine (for meperidine plus naloxone or meperidine plus atipamezole), or fentanyl (for fentanyl plus naloxone) as the first drug, mice were injected with naloxone or atipamezole as the second drug and immediately returned to their cages until start of measurements 20 min later (fig. 1
). To prevent an inappropriate decline of body temperature, cages were warmed by a heating lamp.
Forty minutes after injection of the first drug, mice were positioned in a gas-tight plexiglas chamber (internal diameter, 4 cm; length, 7 cm). A constant oxygen flow of 100 ml/min was delivered to the chamber. Mixed expired carbon dioxide was recorded continuously by capnography (Phasein Multigas sensor; Armeda Medizintechnik, Hannover, Germany). Body temperature was measured and recorded continuously by a rectal temperature probe (Sirecust 402; Siemens, Danvers, MA). Ice was positioned around the plexiglas chamber to provoke a thermoregulatory response by whole body cooling. No animal was allowed to get colder than 32°C. According to previous studies in rats,13
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.
Statistical and Data Analyses
To determine the thermoregulatory threshold, plots of mixed expired carbon dioxide (mmHg) as a function of time were analyzed by three blinded observers and the median value of the three observers was taken for further analysis. Within-group data were analyzed using repeated-measures ANOVA, with Dunnett test for comparison to control (precooling baseline values). Differences between the treatment groups were evaluated using one-way ANOVA followed by Bonferroni correction for multiple comparisons. To analyze differential effects between different genotypes, a 4 × 6 ANOVA was performed. Results are presented as mean ± SD; P < 0.05 was considered significant. GraphPad Prism 5.0 (GraphPad Software, San Diego, CA) was used to perform statistical analyses.
Baseline body temperatures before and after intraperitoneal injection were neither significantly different between mice of all groups, nor between wild-type and α2-adrenoceptor knock-out mice.
In wild-type mice receiving saline, the thermoregulatory threshold temperature was 36.3 ± 0.4°C. Additional injection of naloxone did not change threshold temperature significantly (36.2 ± 0.5°C). After administration of meperidine, the thermoregulatory threshold decreased to 35.0 ± 0.6°C (P
< 0.01). This effect could not be abolished by additional administration of naloxone (35.2 ± 0.7°C) (fig. 2
- and α2C
-adrenoceptor knock-out mice, the thermoregulatory threshold temperature after injection of saline was comparable (36.3 ± 0.7°C vs.
36.3 ± 0.8°C). No significant changes could be detected in both groups after additional injection of naloxone. Administration of meperidine decreased the threshold temperature to 35.3 ± 0.6°C (α2B
-adrenoceptor knock out) (P
< 0.05) and 35.4 ± 0.7°C (α2C
-adrenoceptor knock out) (P
< 0.05), respectively. In α2B
-adrenoceptor knock-out mice, the additional administration of naloxone after meperidine was followed by a minimal and not significant increase of threshold temperature (35.5 ± 0.6°C). In α2C
-adrenoceptor knock-out mice meperidine plus naloxone administration resulted in an alleviated decline of threshold temperature, which was not significant compared with saline administration anymore (fig. 2
In contrast, in α2A
-adrenoceptor knock-out mice, meperidine application alone did not result in a significant decline of the thermoregulatory threshold temperature (36.2 ± 0.6°C vs.
36.5 ± 0.4°C in the saline control group). No significant differences could be detected between threshold temperatures of α2A
-adrenoceptor knock-out mice in all analyzed groups (fig. 2
In wild-type, α2B
-, and α2C
-adrenoceptor knock-out mice, the thermoregulatory threshold after meperidine plus atipamezole injection was significantly higher than after meperidine alone, whereas atipamezole had no effect in α2A
-adrenoceptor knock-out mice. There also was no significant difference between saline control and meperidine plus atipamezole in wild-type, α2B
-, and α2C
-adrenoceptor knock-out mice. This indicates that atipamezole abolished the effects of meperidine in wild-type and α2B
- and α2C
-adrenoceptor knock-out mice (fig. 2
The application of fentanyl plus naloxone had no significant effect on the thermoregulatory threshold temperature in wild-type and α2-adrenoceptor knock-out mice compared with saline control.
An extraordinarily high dose of 1250 μg/kg naloxone compared with 125 μg/kg following saline or meperidine injection had no significant effect on the thermoregulatory threshold temperature in α2C
-adrenoceptor knock-out mice (fig. 3
The maximum response intensity of nonshivering thermogenesis did not show any significant differences between the analyzed groups. Maximum response intensity also was comparable between wild-type and α2
-adrenoceptor knock-out mice (table 1
Finally, the analysis of a differential effect by a 4 × 6 ANOVA revealed no significant interaction between both drugs applied and mice genotype (interaction term, P = 0.2986).
The main findings of our study are as follows:
1. Meperidine decreased the thermoregulatory threshold temperature in wild-type and α2B- and α2C-adrenoceptor knock-out mice. This effect was not abolished by additional administration of the opioid receptor antagonist naloxone but by additional administration of the α2-adrenoceptor antagonist atipamezole.
2. Naloxone had no effect on meperidine-induced decrease of thermoregulatory threshold in wild-type and α2B-adrenoceptor knock-out mice, but did in α2C-adrenoceptor knock-out mice.
3. In contrast, in α2A-adrenoceptor knock-out mice, meperidine had no significant effect on thermoregulatory threshold temperature. Furthermore, naloxone administration did not show any effect.
4. The maximum intensity of nonshivering thermogenesis was comparable in wild-type and α2-adrenoceptor knock-out mice.
The underlying mechanisms of meperidine’s impact on thermoregulation, including the thermoregulatory threshold temperature, remain to be elucidated. In fact, meperidine is more effective in treatment of postanesthetic shivering than equianalgesic doses of other opioids, especially specific μ-opioid receptor agonists.3,14,15
It has been suggested, that additional κ-opioid receptor activation by meperidine was responsible for this effect.4,16
However, even high-dose naloxone expected to block κ-opioid receptors did not completely reverse the antishivering action of meperidine in volunteers.4
In addition to its agonistic effects at opioid receptors, meperidine shows local anesthetic activity and anticholinergic properties,17,18
but this does not fully explain meperidine’s special antishivering action.19
On the other hand, α2
-adrenoceptor agonists such as clonidine or dexmedetomidine have demonstrated their potency in treatment of shivering and their ability in decreasing both the shivering and the vasoconstriction threshold.20
A previous study from our group demonstrated that meperidine decreased the thermoregulatory threshold temperature in wild-type mice. According to our present results, this effect was abolished by administration of the α2
-adrenoceptor antagonist atipamezole, indicating an involvement of α2
-adrenoceptors in the mediation of meperidine actions.10
This conclusion is supported by the fact that meperidine acts as an agonist at α2
-adrenoceptors in vitro
in clinically relevant concentrations, showing highest affinity to the α2B
-adrenoceptor subtype (α2B
, 8.6 ± 0.3 μm; α2C
, 13.6 ± 1.5 μm; α2A
, 38.6 ± 0.7 μm).5
As a result of these in vitro
binding studies, mice with modified α2
-adrenoceptor genes have become important tools in elucidating α2
-adrenoceptor subtype-specific functions. In agreement with our results with meperidine, Hunter et al.8
did not detect hypothermic effects in mice with a functional α2A
-adrenoceptor knock out in response to varying doses of dexmedetomidine. In contrast, in wild-type and α2B
- and α2C
-adrenoceptor knock-out mice, thermoregulation was influenced, whereas Sallinen et al.21
reported a slight attenuation of the hypothermic response in α2C
-adrenoceptor knock-out mice. These results point to the α2A
-adrenoceptor as the primary mediator of the thermoregulatory effects of α2
-adrenoceptor agonists, although the α2C
-adrenoceptor subtype also may be involved.9
In our study, in α2A-adrenoceptor knock-out mice no significant decline of the thermoregulatory threshold temperature after meperidine administration could be detected, whereas the threshold temperature decreased in wild-type- and α2B- and α2C-adrenoceptor knock-out mice. The fact that this decrease in wild-type and α2B-adrenoceptor knock-out mice was not abolished by naloxone but atipamezole administration indicates that nonopioid receptor pathways are involved.
To rule out that the high naloxone dose4
that we applied was too small and not capable of blocking all μ- and κ-opioid receptors, we compared the effects of 125 μg/kg versus
1,250 μg/kg naloxone without any significant difference. Average duration of our experiments from naloxone administration was 45 min, so a repetitive injection seemed unnecessary. On the other hand, meperidine plus naloxone injection led to a small increase of threshold temperature compared with meperidine alone in α2C
-adrenoceptor knock-out mice. In α2B
-adrenoceptor knock-out mice, this tendency also was detectable but not significant. This indicates that opioid receptors—possibly the κ-subtype—in addition are likely to be involved in the mediation of meperidine’s effects.
From the current data, no change of the maximum response intensity of shivering as the ratio of the maximum and minimum carbon dioxide plateau during cooling could be observed. In agreement with our results, Ikeda et al.22
did not detect any changes in the maximum intensity of shivering after meperidine and also alfentanil application. However, both drugs proved to decrease the thermoregulatory threshold. This indicates that antishivering activity does not necessarily include both an effect on the thermoregulatory threshold and on the maximum intensity or gain (defined as incremental intensity increase) of shivering.
Our study may be criticized because of the relatively small number of animals investigated, resulting in a certain variability of the results. Furthermore, naloxone was initially administered in only one defined high dosage to block both μ- and κ-opioid receptors, according to previous studies in humans and mice.4
Small differences between meperidine and meperidine plus naloxone may not have been detected as result of the sample size. As a result, we cannot conclude that the effects of meperidine on thermoregulation in mice are mediated exclusively by α2
-adrenoceptors. Furthermore, data from animal studies should be projected to humans with some limitations. Whereas adult humans use shivering as a defense against hypothermia and nonshivering thermogenesis plays only a small role, rodents use nonshivering thermogenesis as their primary mechanism to resist hypothermia. Therefore, it should be clearly stated that our results in mice have only very limited impact on the peri- or postoperative thermoregulation in humans.
In conclusion, the present data indicate that meperidine’s ability to decrease the thermoregulatory threshold temperature in wild-type mice is not abolished by additional administration of the opioid receptor antagonist naloxone. In α2A-adrenoceptor knock-out mice, meperidine administration had no significant effect on the thermoregulatory threshold temperature. This indicates an important role of the α2A-adrenoceptor in the modulation of the thermoregulatory response induced by meperidine in mice.
The authors thank Lutz Hein (Professor, Institute of Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany) for providing the α2-adrenoceptor knock-out mice for this study, and Maria Kiosz (Technician, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany) for her help.
1. Sessler DI: Perioperative thermoregulation and heat balance. Ann NY Acad Sci 1997; 813:757–77
2. Alfonsi P: Postanaesthetic shivering: Epidemiology, pathophysiology, and approaches to prevention and management. Drugs 2001; 61:2193–205
3. Kurz A, Ikeda T, Sessler DI, Larson MD, Bjorksten AR, Dechert M, Christensen R: Meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold. Anesthesiology 1997; 86:1046–54
4. Kurz M, Belani KG, Sessler DI, Kurz A, Larson MD, Schroeder M, Blanchard D: Naloxone, meperidine, and shivering. Anesthesiology 1993; 79:1193–201
5. Takada K, Clark DJ, Davies MF, Tonner PH, Krause TK, Bertaccini E, Maze M: Meperidine exerts agonist activity at the α(2B)-adrenoceptor subtype. Anesthesiology 2002; 96:1420–6
6. Joris J, Banache M, Bonnet F, Sessler DI, Lamy M: Clonidine and ketanserin both are effective treatment for postanesthetic shivering. Anesthesiology 1993; 79:532–9
7. Macintyre PE, Pavlin EG, Dwersteg JF: Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanesthesia shivering. Anesth Analg 1987; 66:751–5
8. Hunter JC, Fontana DJ, Hedley LR, Jasper JR, Lewis R, Link RE, Secchi R, Sutton J, Eglen RM: Assessment of the role of α2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br J Pharmacol 1997; 122:1339–44
9. Kable JW, Murrin LC, Bylund DB: In vivo gene modification elucidates subtype-specific functions of α(2)-adrenergic receptors. J Pharmacol Exp Ther 2000; 293:1–7
10. Paris A, Ohlendorf C, Marquardt M, Bein B, Sonner JM, Scholz J, Tonner PH: The effect of meperidine on thermoregulation in mice: Involvement of α2-adrenoceptors. Anesth Analg 2005; 100:102–6
11. Link RE, Desai K, Hein L, Stevens ME, Chruscinski A, Bernstein D, Barsh GS, Kobilka BK: Cardiovascular regulation in mice lacking α2-adrenergic receptor subtypes b and c. Science 1996; 273:803–5
12. Altman JD, Trendelenburg AU, MacMillan L, Bernstein D, Limbird L, Starke K, Kobilka BK, Hein L: Abnormal regulation of the sympathetic nervous system in α2A-adrenergic receptor knockout mice. Mol Pharmacol 1999; 56:154–61
13. Maurer AJ, Sessler DI, Eger EI 2nd, Sonner JM: The nonimmobilizer 1,2-dichlorohexafluorocyclobutane does not affect thermoregulation in the rat. Anesth Analg 2000; 91:1013–6
14. Alfonsi P, Hongnat JM, Lebrault C, Chauvin M: The effects of pethidine, fentanyl and lignocaine on postanaesthetic shivering. Anaesthesia 1995; 50:214–7
15. Alfonsi P, Sessler DI, Du Manoir B, Levron JC, Le Moing JP, Chauvin M: The effects of meperidine and sufentanil on the shivering threshold in postoperative patients. Anesthesiology 1998; 89:43–8
16. Magnan J, Paterson SJ, Tavani A, Kosterlitz HW: The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties. Naunyn Schmiedebergs Arch Pharmacol 1982; 319:197–205
17. Horn EP, Standl T, Sessler DI, von Knobelsdorff G, Buchs C, Schulte am Esch J. Physostigmine prevents postanesthetic shivering as does meperidine or clonidine. Anesthesiology 1998; 88:108–13
18. Wagner LE 2nd, Eaton M, Sabnis SS, Gingrich KJ: Meperidine and lidocaine block of recombinant voltage-dependent Na+ channels: Evidence that meperidine is a local anesthetic. Anesthesiology 1999; 91:1481–90
19. Greif R, Laciny S, Rajek AM, Larson MD, Bjorksten AR, Doufas AG, Bakhshandeh M, Mokhtarani M, Sessler DI: Neither nalbuphine nor atropine possess special antishivering activity. Anesth Analg 2001; 93:620–7
20. Talke P, Tayefeh F, Sessler DI, Jeffrey R, Noursalehi M, Richardson C: Dexmedetomidine does not alter the sweating threshold, but comparably and linearly decreases the vasoconstriction and shivering thresholds. Anesthesiology 1997; 87:835–41
21. Sallinen J, Link RE, Haapalinna A, Viitamaa T, Kulatunga M, Sjoholm B, Macdonald E, Pelto-Huikko M, Leino T, Barsh GS, Kobilka BK, Scheinin M: Genetic alteration of α 2C-adrenoceptor expression in mice: Influence on locomotor, hypothermic, and neurochemical effects of dexmedetomidine, a subtype-nonselective α 2-adrenoceptor agonist. Mol Pharmacol 1997; 51:36–46
22. Ikeda T, Sessler DI, Tayefeh F, Negishi C, Turakhia M, Marder D, Bjorksten AR, Larson MD: Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering. Anesthesiology 1998; 88:858–65
© 2008 American Society of Anesthesiologists, Inc.