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BJA Advance Access originally published online on March 10, 2006
British Journal of Anaesthesia 2006 96(5):597-601; doi:10.1093/bja/ael046
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Ketamine, but not propofol, anaesthesia is regulated by metabotropic glutamate 5 receptors

J.-H. Sou1,2, M.-H. Chan1 and H.-H. Chen1,*

1 Institute of Pharmacology and Toxicology, Tzu Chi University Hualien, Taiwan, R.O.C
2 Department of Health, Yuli Hospital Executive Yuan, Hualien, Taiwan, R.O.C.

*Corresponding author: Institute of Pharmacology and Toxicology, Tzu Chi University, 701, Section 3, Chung-Yang Road, Hualien, 970, Taiwan, R.O.C. E-mail: hwei{at}mail.tcu.edu.tw

Accepted for publication January 6, 2006.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background. Group I metabotropic glutamate receptors (mGluRs) have been reported to regulate N-methyl-D-aspartate (NMDA) receptor function in various brain regions. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate NMDA antagonists such as PCP and MK-801-induced behavioural responses. In the present study, the role of group I mGluRs on ketamine- and propofol-induced general anaesthesia was examined.

Methods. Mice were pretreated with various doses of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG), selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) and mGluR5 antagonist MPEP followed by administration of ketamine (120 mg kg–1) or propofol (140 mg kg–1) to induce anaesthesia. The duration of loss of righting reflex was recorded.

Results. DHPG and CHPG antagonized and MPEP potentiated ketamine-induced anaesthesia in a dose-dependent manner. CPCCOEt was ineffective. However, propofol-induced anaesthesia was not affected after manipulating mGluR1 and mGluR5 receptors.

Conclusions. mGluR5 receptors play an important role in modulation of anaesthesia induced by ketamine, but not propofol.

Keywords: anaesthesia; anaesthetics i.v., ketamine; anaesthetics i.v., propofol; receptors, mGluR1; receptors, mGluR5


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Ketamine and propofol are i.v. general anaesthetics used in clinical practice. Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Unlike ketamine, propofol exhibits prominent GABAergic actions. There is accumulating evidence that group I mGluRs (mGluR1 and mGluR5) are physically connected with NMDA and GABAA receptors and their stimulation positively modulates the function of NMDAergic1–7 and GABAergic synapses8–11 in several brain regions. Recently, it has been demonstrated that antagonists of mGluR5, but not mGluR1, augmented non-competitive NMDA receptor antagonists, PCP- and MK-801-induced behavioural responses.12–14 It is of interest to know if group I mGluRs modulate anaesthesia induced by ketamine and propofol.

The aim of the present study was to examine the role of group I mGluRs in anaesthesia induced by ketamine and propofol. For this purpose, the effects of (S)-3,5-dihydroxyphenylglycine (DHPG), a selective group I mGluR agonist, (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), the specific mGluR5 receptor agonist, the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) and mGluR5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) on the duration of ketamine- and propofol-induced loss of righting reflex (LORR) were examined.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Animals and drugs
Male NMRI mice (8–9 weeks, 33–40 g) were supplied from the Laboratory Animal Center of Tzu Chi University (Hualien, Taiwan) and housed 4–5 per cage in a 12 h light/dark cycle with access to water and food ad libitum. The experimental protocol was approved by the Review Committee of the Tzu Chi University for the Use of Animals. Animals were randomly assigned to receive either ketamine (n=90) or propofol (n=72). Each group was further randomly distributed into four experimental sets for DHPG, CHPG, CPCCOEt or MPEP treatment. Each experimental set included an artificial cerebrospinal fluid (ACSF) group and various concentration groups (n=6). Each animal was examined only once.

Propofol (Fresofol 1%®, Fresenius Kabi Austria GmbH) and ketamine (Sigma, MO, USA) were diluted in saline. CHPG (Tocris, Bristol, UK) was dissolved in 0.5 N NaOH, MPEP (Sigma, MO, USA) was dissolved in 10% Tween 20, CPCCOEt (Tocris, Bristol, UK) was dissolved in dimethyl sulphoxide (final concentration 0.5–2%) and diluted in ACSF containing (in mM) NaCl (120), KCl (5), CaCl2 (1.5), MgCl2 (0.8), Na2HPO4 (1.4) and NaH2PO4 (0.25) at pH 7.4.

Intracerebroventricular (i.c.v.) injection was administered following a procedure established previously.15 Briefly, each conscious mouse was grasped firmly by the loose skin behind the head and its snout was gently pushed into the mouth of a barrel of a 5 ml syringe, which was horizontally fixed on the edge of a table. The animal was injected at the bregma with a 10 µl Hamilton syringe, fitted with a 26 gauge needle that was inserted to a depth of 2.4 mm. Bregma could be found about 1–3 mm rostral to a line drawn between the anterior base of the ears after feeling the suture line by lightly rubbing the point of a needle. The volume of i.c.v. injections was 5 µl. Insertion of the needle and injection of ACSF had a slight effect on the mice. Immediately after removal of the needle, the animals remained quiet for approximately 30 s and then resumed their normal activity.

Various concentrations of DHPG, CHPG, MPEP and CPCCOEt were administered i.c.v. 5 min before administration of ketamine or propofol to induce LORR.

Loss of righting reflex test
Following intraperitoneal (i.p.) injection of ketamine (120 mg kg–1) or propofol (140 mg kg–1), mice were replaced in a clean cage until the righting reflex was lost. They were then placed in the supine position until recovery and the duration of the LORR was recorded. Recovery of the righting reflex was defined as the ability to perform three successive rightings.

Statistical analyses
Data were analysed by one-way ANOVA followed by Newman–Keuls test. P<0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Ketamine (120 mg kg–1, i.p.) produced a LORR for 12–15 min. As shown in Figure 1, pretreatment (i.c.v.) with either the group I mGluR agonist DHPG (5–50 nmol) or mGluR5 agonist CHPG (0.5–5 nmol) reduced the duration of ketamine-induced anaesthesia in a dose-dependent manner. However, the mGluR1 antagonist CPCCOEt (5–500 nmol) did not produce affect ketamine-induced anaesthesia (Fig. 2A). In contrast, the mGluR5 antagonist MPEP (100–200 nmol) potentiated ketamine-induced anaesthesia (Fig. 2B). Propofol (140 mg kg–1) produced LORR for 30–40 min. Manipulating mGluR1 and mGluR5 by pretreatment with DHPG, CHPG, CPCCOEt and MPEP did not affect the propofol-induced anaesthesia (Figs 3 and 4).


Figure 1
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  		Fig 1 Dose-dependent effect of DHPG and CHPG on ketamine-induced anaesthesia. Mice were pretreated with ACSF, DHPG (5 and 50 nmol, i.c.v.) (A) or CHPG (0.5, 2.5 and 5 nmol, i.c.v.) (B) and the duration of LORR was recorded after administration of ketamine (120 mg kg–1, i.p.). All values are expressed as the mean (SEM) (n=6). One-way ANOVA: F(2,15)=7.098, P=0.0068 for DHPG; F(3,20)=18.91, P<0.0001 for CHPG; *P<0.05, **P<0.01, ***P<0.001 compared with the vehicle control (Student–Newman–Keuls test).

 

Figure 2
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  		Fig 2 Dose-dependent effect of CPCCOEt and MPEP on ketamine-induced anaesthesia. Mice were pretreated with ACSF, CPCCOEt (5, 50 and 500 nmol, i.c.v.) (A) or MPEP (50, 100 and 200 nmol, i.c.v.) (B) and the duration of LORR was recorded after administration of ketamine (120 mg kg–1, i.p.). All values are expressed as the mean (SEM) (n=6). One-way ANOVA: F(3,20)=2.762, P=0.07 for CPCCOEt; F(3,20)=13.77, P<0.0001 for MPEP. ***P<0.001 compared with the vehicle control (Student–Newman–Keuls test).

 

Figure 3
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  		Fig 3 Dose-dependent effect of DHPG and CHPG on propofol-induced anaesthesia. Mice were pretreated with ACSF, DHPG (5 and 50 nmol, i.c.v.) (A) or CHPG (5 and 50 nmol, i.c.v.) (B) and the duration of LORR was recorded after administration of propofol (140 mg kg–1, i.p.). All values are expressed as the mean (SEM) (n=6). One-way ANOVA: F(2,15)=0.476, P=0.63 for DHPG; F(2,15)=0.727, P=0.499 for CHPG.

 

Figure 4
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  		Fig 4 Dose-dependent effect of CPCCOEt and MPEP on propofol-induced anaesthesia. Mice were pretreated with ACSF, CPCCOEt (50 and 500 nmol, i.c.v.) (A) or MPEP (50 and 200 nmol, i.c.v.) (B) and the duration of LORR was recorded after administration of propofol (140 mg kg–1, i.p.). All values are expressed as the mean (SEM) (n=6). One-way ANOVA: F(2,15)=0.133, P=0.87 for CPCCOEt; F(2,15)=0.542, P=0.59 for MPEP.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the present study, we have examined the effects of a selective Group I mGluR agonist DHPG, mGluR5 receptor agonist CHPG, the mGluR1 antagonist CPCCOEt and mGluR5 receptor antagonist MPEP on ketamine and propofol anaesthesia in mice. Our results indicated that pretreatment with group I mGluR agonist DHPG and mGluR5 receptor agonist CHPG reduced, whereas mGluR5 antagonist MPEP prolonged the duration of LORR-induced by ketamine. However, mGluR1 antagonist did not affect ketamine-induced anaesthesia. In contrast, these agonists and antagonists of mGluR1 and mGluR5 did not modify propofol-induced anaesthesia.

Although both mGluR1 and mGluR5 are physically connected with NMDA receptors and their stimulation positively modulates the function of NMDA receptors in several brain regions,1–7 several behavioural responses induced by non-competitive NMDA receptor antagonists, such as MK-801 and PCP, are potentiated by the mGluR5 antagonists, MPEP or MTEP,12–14 16 but not modified by mGluR1 antagonist. Consistent with the behavioural responses induced by NMDA antagonists, anaesthesia induced by ketamine was modified by agents acting on mGluR5, but not those acting on mGluR1.

On a biochemical level, group I mGluRs, including mGluR1 and mGluR5, are positively coupled to phospholipid-dependent protein kinase C (PKC) and calcium signalling pathways.17–19 However, it has been found that mGluR1 and mGluR5 exhibit a distinct plasma membrane distribution and location in several brain areas, which suggests that those receptors might have a different role in the central nervous system.20–23 Functional segregation between mGluR1 and mGluR5 has been found. Consistent with the enhancing effects mGluR5 but not mGluR1 antagonists, on MK-801-induced locomotor activity and deficit of prepulse inhibition,12 the present study demonstrated that manipulating mGluR5, but not mGluR1 altered ketamine-induced anaesthesia. It has been suggested that mGluR5, but not mGluR1 could interact with NMDA receptor to modify the behavioural responses induced by non-competitive NMDA receptor antagonists. The molecular mechanism that mediates the action of mGluR5 on NMDA receptors involves tyrosine phosphorylation of the receptor via a signalling cascade involving phospholipase C (PLC), PKC and Src.7 It is not known, however, whether tyrosine phosphorylation of NMDA receptors reduced the efficacy of non-competitive NMDA receptor antagonists. Further studies are needed to determine whether mGluR5 agents might alter the anaesthetic effect of ketamine via modification of the tyrosine phosphorylation of NMDA receptors. Pharmacokinetic interactions between mGluR agents and ketamine may exist, however we feel this possibility is very low. The effect of mGluR agents on the metabolism of ketamine may be avoided by i.c.v. injection. If these i.c.v. injected agents have cardiovascular effects to alter the disposition kinetics of ketamine, they should also affect those of propofol, leading to alterations in the duration of propofol-induced LORR. However, our data did not show any effect of mGluR agents on propofol-induced LORR.

Unlike ketamine, propofol exhibits a prominent GABAergic action which is believed to be involved in its anaesthetic activity.24–26 It has been reported that mGluR5 and GABAA {alpha}1-containing receptors are both co-expressed in limbic brain regions and co-localized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus and ventral pallidum.27 Furthermore, an interaction between mGluR5- and benzodiazepine-sensitive GABAA receptors may play a role in the discriminative stimulus effects of ethanol.27 Accordingly, it is possible that modulation of mGluR5 may also affect propofol-induced anaesthesia. However, our data showed that the mGluR5 agonist CHPG and antagonist MPEP did not affect the propofol-induced anaesthesia. Thus, the lack of effect of mGluR1 and mGluR5 agents on propofol may be because of a lack of receptor expression in relevant brain regions or an expression pattern unable to influence propofol-induced LORR. Whilst no interaction was found between mGluR agents and propofol on LORR, it is possible and remains to be determined if mGluR agents affect the other propofol-induced anaesthetic endpoints, such as antinociception or electroencephalographic burst suppression. It is noted that the duration of LORR-induced by propofol was twice as long as that induced by ketamine, thus we cannot rule out the possibility that the inability to affect the propofol-induced LORR with mGluR agents is because of the stronger effect of the dose of propofol relative to ketamine. However, this possibility is extremely low as large doses of mGluR agonists and antagonists did not modify the effect of propofol. It will be more useful to examine the effect of mGluR agents on potency (ED50) for each anaesthetic rather than the duration of LORR-induced by a single dose.

In conclusion, our results demonstrate that the activation and inhibition of mGluR5, but not mGluR1, alter anaesthesia induced by ketamine. Thus, the distinct physiological functions of mGluR1 and mGluR5 are emphasized by the present data. In addition, the agonists and antagonists of mGluR1 and mGluR5 did not affect the propofol-induced anaesthesia, indicating the different neural modulation during anaesthesia induced by ketamine and propofol.


   Acknowledgments
 
This work was supported by a grant from National Scientific Council, Taiwan (NSC 93-2745-B-320-003-URD).


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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