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Anesth Analg 2003;97:104-110
© 2003 International Anesthesia Research Society

ANESTHETIC PHARMACOLOGY

The Inhibitory Effects of Ketamine and Pentobarbital on Substance P Receptors Expressed in Xenopus Oocytes

Takashi Okamoto, MD*, Kouichiro Minami, MD PhD*, Yasuhito Uezono, MD PhD{ddagger}, Junichi Ogata, MD*, Munehiro Shiraishi, MD*, Akio Shigematsu, MD PhD*, and Yoichi Ueta, MD PhD{dagger}

Departments of *Anesthesiology and {dagger}Physiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu; {ddagger}Department of Pharmacology, Nagasaki University, Graduate School of Biomedical Sciences, Japan

Address correspondence and reprint requests to Kouichiro Minami, MD, PhD, Department of Anesthesiology, University of Occupational and Environmental Health School of Medicine, 1-1, Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807-8555, Japan. Address e-mail to kminami{at}med.uoeh-u.ac.jp


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Substance P receptors (SPR) modulate nociceptive transmission within the spinal cord. The effects of IV anesthetics on SPR are not clear. In this study, we investigated the effects of IV anesthetics on SPR expressed in Xenopus oocytes. We examined the effects of ketamine, pentobarbital, propofol, and tramadol on SP-induced Ca2+-activated Cl- currents mediated by SPR expressed in Xenopus oocytes using a whole-cell voltage clamp. Ketamine and pentobarbital inhibited the SPR-induced currents at pharmacologically relevant concentrations, but propofol and tramadol had little effect on the currents. We also studied the effects of ketamine and pentobarbital on [3H]-SP to SPR. Ketamine and pentobarbital inhibited the specific binding of [3H]-SP to SPR expressed in Xenopus oocytes. Scatchard analysis of [3H]-SP binding revealed that ketamine and pentobarbital decreased the apparent dissociation constant for binding and maximal binding, indicating noncompetitive inhibition. The protein kinase C (PKC) inhibitor bisindolylmaleimide I did not abolish the inhibitory effects of ketamine and pentobarbital on SP-induced Ca2+-activated Cl- currents. The results suggest that ketamine and pentobarbital inhibit SPR function. The mechanism of their inhibition on SPR function could not be through activation of the PKC pathway and may be due to noncompetitive displacing the SP binding.

IMPLICATIONS: We investigated the effects of IV anesthetics on substance P receptors (SPR) expressed in Xenopus oocytes. Ketamine and pentobarbital inhibit SPR function via noncompetitive displacing SP binding. The findings imply that the inhibition of SPR function by these compounds may play a role in the analgesic effects of these IV anesthetics.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
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 References
 
Substance P (SP) acts as a neurotransmitter released from C fibers found within nociceptive primary afferent neurons into the spinal cord and mediates a part of the excitatory synaptic input to nociceptive neurons at this level (1,2). SP and its receptors (SPR) are widely distributed in the central and peripheral nervous systems (3). Several studies showed that pain sensitivity is altered in mice lacking the gene encoding SPR; a reduction in nociceptive responses to certain somatic and visceral noxious stimuli occurs in SPR knockout mice (4,5).

SPR belongs to the family of G protein-coupled receptors, and, when activated, myo-inositol-1,4,5-trisphosphate (IP3) and diacylglycerol are produced by activating phospholipase C. Our report has shown that the function of SPR is inhibited by volatile anesthetics, such as halothane, isoflurane, enflurane, diethyl ether, and ethanol, in Xenopus oocytes expressing SPR, suggesting that SPR is one of the targets of some volatile anesthetics and ethanol (6). In contrast, the effects of IV anesthetics on SPR have not been studied.

The Xenopus oocyte expression system has been used to study a multiplicity of brain receptors with pharmacological properties that mimic those of native brain receptors (7). Stimulation of SPR results in activation of Ca2+-activated Cl- currents in Xenopus oocytes (6); stimulation of SPR leads to G protein-dependent activation of phospholipase C, resulting in the formation of IP3 and diacylglycerol. IP3 causes the release of Ca2+ from the endoplasmic reticulum, which in turn triggers the opening of Ca2+-activated Cl- channels in Xenopus oocytes. This system has been well characterized and has proven useful for studying the effects of IV anesthetics on G protein-coupled receptors.

The purpose of this study was to examine the effects of the IV anesthetics, ketamine, pentobarbital, propofol, and tramadol on the SP-induced Ca2+-activated Cl- currents in Xenopus oocytes expressing SPR. We further investigated the effects of these anesthetics on SP binding to SPR expressed in Xenopus oocytes.


   Materials and Methods
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 Abstract
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 Materials and Methods
Results
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 References
 
Adult Xenopus laevis female frogs were purchased from Seac Yoshitomi (Yoshitomi, Fukuoka, Japan); SP, ketamine, and pentobarbital were from Sigma (St Louis, MO). Tramadol hydrochloride was a kind gift from Nippon Shinyaku (Kyoto, Japan). Propofol was from Tokyo kasai (Tokyo, Japan), bisindolylmaleimide I (GF109203X) was from Calbiochem (La Jolla, CA), and the Ultracomp Escherichia coli Transformation Kit was from Invitrogen (San Diego, CA). A Qiagen (Chatworth, CA) Kit was used to purify plasmid complimentary (c)DNA. Rat SPR cDNA was kindly provided by Dr. J.E. Krause (Washington University School of Medicine, St Louis, MO). The cDNA for the SPR was inserted into the pBlueScriptIISK(-) vector and linearized with XbaI. The SPR cRNA was prepared by using an mCAP messenger RNA Capping Kit and transcribed with a T7 RNA Polymerase in vitro Transcription Kit (Stratagene, La Jolla, CA).

Isolation and microinjection of Xenopus oocytes were performed as described by Sanna et al (8). Briefly, Xenopus oocytes were injected with 50 ng of cRNA encoding SPR and incubated for 2 days. Oocytes were placed in a 100 µL recording chamber and perfused with modified Barth’s saline (MBS) containing 88 mM of NaCl, 1 mM of KCl, 2.4 mM of NaHCO3, 10 mM of HEPES, 0.82 mM of MgSO4, 0.33 mM of Ca(NO3)2, and 0.91 mM of CaCl2 (pH value of 7.5) at a rate of 1.8 mL/min at room temperature. Recording and clamping electrodes (1–5 M{Omega}) were pulled from 1.2-mm outside diameter capillary tubing and filled with 3 M of KCl. A recording electrode was imbedded in the animal’s pole, and once the resting membrane potential stabilized, a clamping electrode was inserted, and the resting membrane potential was allowed to restabilize. A Warner OC 725-B oocyte clamp (Hampden, CT) was used to voltage-clamp each oocyte at -70 mV. We analyzed the peak of the transient inward current component of the SPR-induced currents because this component is dependent on SP concentration and is quite reproducible, as described by Minami et al (6). The IV anesthetics (ketamine, pentobarbital, and propofol) and tramadol were preapplied for 2 min to allow for complete equilibration in the bath. The solutions of IV anesthetics were freshly prepared immediately before use. The concentrations in the figures represent the bath concentrations.

To determine whether activation of protein kinase C (PKC) plays a role in anesthetic modulation of SPR-mediated events, oocytes were exposed to a PKC inhibitor, bisindolylmaleimide I (GF109203X)(200 nM) (9), in MBS for 120 min. We compared the effects of anesthetics on SP-induced Ca2+-activated Cl- currents in Xenopus oocytes expressing SPR before and after the exposure to GF109203X.

AlF4- was used as a direct activator of G proteins, and with this system, we could bypass the signal to G proteins from activated receptors. Under a two-electrode voltage clamp, we injected 30 nL of solution containing NaF and AlCl3 into the oocyte by using a pressure injector (PM2000B; MicroData Instruments, South Plainfield, NJ). The concentrations of NaF and AlCl3 used in this study were 20 mM and 60 µM.

Binding experiments of [3H]-SP (Perkin Elmer Life Sciences, Tokyo, Japan) to Xenopus oocytes were performed, as described by Shiga et al. (10). Xenopus oocytes were injected with 50 ng of cRNA encoding the SPR and incubated for 2 days. A single oocyte was incubated for 60 min at 25°C with MBS (final volume 0.5 mL) containing [3H]-SP (0.1–0.5 nM) in the presence or absence of ketamine or pentobarbital. Three oocytes per one tube were used for total binding and nonspecific binding at a concentration of ketamine (100 µM) or pentobarbital (100 µM), respectively. After incubation, binding was terminated, and the oocyte was rapidly washed four times with 5 mL of ice-cold MBS buffer under vacuum through Whatman GF/C glass-fiber filters (Whatman Inc, Clifton, NJ) and then placed in counting vials containing a scintillation cocktail. The radioactivity was counted in an Aloka LSC-3500E counter (Aloka Co, Tokyo, Japan). Specific binding of [3H]-SP was defined as the binding inhibited by 10 µM of SP.

The results are expressed as percentage of control responses caused by the variable SPR expression rate in oocytes. The control responses were measured before and after application of each test compound to take into account possible shifts in the control currents as recording proceeded. The n values refer to the number of oocytes studied. Each experiment was performed with oocytes from at least two different frogs. Statistical analyses were performed using a one-way analysis of variance. Curve fitting and estimation of half-maximal inhibitory concentration values for concentration-response curves were performed using Graphpad Prism Software (San Diego, CA).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
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Both ketamine and pentobarbital inhibited the Cl- currents activated by SP (Figs. 1 and 2). Ketamine inhibited the action of 100 nM of SP to 93.4% ± 2.0%, 80.7% ± 6.1%, and 63.0% ± 7.8% of the control at concentrations of 0.01, 0.1, and 1 mM, respectively. Pentobarbital inhibited the currents activated by SP to 60.7% ± 11%, 58.5% ± 13.6%, and 38.2% ± 13.6% of the control at 0.01, 0.1, and 1 mM, respectively. However, propofol and tramadol did not have inhibitory effects on SP-induced Ca2+-activated Cl- currents. After washout of these anesthetics, the SPR-induced currents were stabilized to the same as controls.



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  		Figure 1. Effects of ketamine, pentobarbital, propofol, and tramadol on substance P (SP)-stimulated currents in Xenopus oocytes expressing SP receptors (SPR). Tracings obtained from a single oocyte expressing SPR show the effect of ketamine (Ket.) (A), pentobarbital (Pent.) (B), propofol (Prop.) (C), and tramadol (Tra.) (D) on 100 nM of SP-induced currents. SP was applied for 20 s with or without 2-min treatment with 100 µM of ketamine, pentobarbital, propofol, and tramadol, respectively.

 


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  		Figure 2. Concentration-response relationship of ketamine, pentobarbital, propofol, and tramadol on substance P (SP)-induced currents. Ketamine (1 µM–1 mM), pentobarbital (1 µM–1 mM), propofol (100 nM–100 µM), and tramadol (100 nM–100 µM) were applied to the oocytes for 2 min, and then 100 nM of SP was applied for 20 s. Data represent the mean ± SEM of 40 oocytes. **P < 0.01 and ***P < 0.001 compared with the control response using analysis of variance.

 
Treatment with a PKC inhibitor, GF109203X (200 nM), which has a Ki value for inhibiting PKC activity of 20 nM (9), produced the enhancement of the initial Cl- currents activated by 100 nM of SP (Fig. 3), which were consistent with the reports by Minami et al (6). The inhibitory effects of ketamine and pentobarbital on SP-induced currents were observed in the oocytes pretreated with GF109203X (Fig. 3).



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  		Figure 3. Effects of bisindolylmaleimide I (GF109203X) on the inhibitory effects of ketamine and pentobarbital on substance P (SP)-induced currents. (A) Tracings were obtained from a single oocyte showing the effect of ketamine (Ket.) and pentobarbital (Pent.) on 100 nM of SP-induced currents in oocytes expressing SP receptor (SPR) before and after treatment with GF109203X. Oocytes were incubated with 200 nM of GF109203X for 2 h and were then stimulated by SP in the presence of ketamine (100 µM) and pentobarbital (100 µM). (B) The effects of ketamine (100 µM) and pentobarbital (100 µM) on 100 nM of SP-induced currents with or without GF109203X (200 nM) pretreatment. Values are the mean ± SEM of 15 oocytes.

 
AlF4- binds to guanosine diphosphate on heterotrimeric G protein, and guanosine diphosphate-AlF4- complex promotes the dissociation of heterotrimeric G proteins into G{alpha} and Gß{gamma} subunits, which subsequently leads to the activation of G protein (11). The peak amplitude of AlF4--induced currents was 117.2 ± 48 nA (n = 5), and ketamine did not affect the AlF4--induced currents (98.2 ± 32 nA; n = 5) (Fig. 4A). Pentobarbital also did not affect the AlF4--induced currents (136.3 ± 58 nA; n = 5) (Fig. 4B) (the peak amplitude of AlF4--induced currents was 167 ± 43 nA; n = 5).



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  		Figure 4. Effects of ketamine and pentobarbital on AlF4--induced currents in Xenopus oocytes. (A) Tracings were obtained from a single oocyte showing the effect of ketamine and pentobarbital on AlF4--induced currents in oocytes expressing substance P receptor (SPR). (B) Oocytes were injected with 30 nL of test solution (20 mM of NaF and 60 µM of AlCl3) in the presence (n = 5) or absence (n = 5) of 10 µM of ketamine or 10 µM of pentobarbital. Values are expressed as the mean ± SEM.

 
Specific binding of [3H]-SP was saturable with increasing concentration of [3H]-SP (0.1–0.5 nM; Fig. 5). Scatchard analysis showed a single population of binding sites with an apparent dissociation constant (Kd) of 0.3 nM and maximal binding (Bmax) of 12.5 pmol/3 oocytes (Fig. 5B). The specific binding of [3H]-SP was inhibited by 100 µM of ketamine, and this was not reversed by increasing the concentration of [3H]-SP (Fig. 5). The specific binding of [3H]-SP was also inhibited by 100 µM of pentobarbital, and this was not reversed by increasing the concentration of [3H]-SP, as was the case with ketamine (Fig. 5). From the results of the Scatchard analysis, ketamine decreased the Kd value of [3H]-SP binding (0.2 nM) without changing Bmax (9 pmol/3 oocytes) (Fig. 5B). In the presence of pentobarbital, the Kd value of [3H]-SP binding was 0.16 nM, and changing Bmax was 6.2 pmol/3 oocytes (Fig. 5B).



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  		Figure 5. Saturation and Scatchard analyses of [3H]-substance P (SP) binding to SP receptor (SPR) expressed in Xenopus oocytes. (A) Oocytes (three oocytes/tube) expressing SPR were incubated for 60 min at 25°C in the presence of ketamine (10 µM) (•) and pentobarbital (10 µM) ({square}) or absence ({circ} of anesthetics with increasing concentrations of [3H]-SP (0.1–0.5 nM). Data shown are the mean ± SEM of 10 separate experiments performed in duplicate. (B) Scatchard analysis of specific binding of [3H]-SP. The data are from Figure 5A.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our results demonstrate that ketamine and pentobarbital, but not propofol and tramadol, inhibited the function of SPR. When ketamine was used clinically, the free plasma concentration of ketamine 5 minutes after IV injection of 2.5 mg/kg was approximately 10.5 µM (12), and a much larger concentration of ketamine in free plasma (60 µM) was also demonstrated in patients after the IV injection of 2 mg/kg (13). The plasma concentration of pentobarbital reaches a maximum of 1.49 µg/mL (approximately 6 µM) in patients receiving a continuous infusion of pentobarbital. Therefore, ketamine and pentobarbital would inhibit SPR function at clinically relevant concentrations.

Ketamine depresses the tail-immersion and the hot-plate test response in mice. The response observed in the tail-immersion test is regarded as a spinal reflex and is appropriate for detection of spinally-mediated antinociception (14). The hot-plate test is considered supraspinal in that it requires an intact central nervous system and is appropriate for detection of supraspinally mediated antinociception (5). Barbiturates have been characterized as nonanalgesic or even hyperalgesics (15); however, several studies have suggested that barbiturates may be effective analgesic at the spinal level, at least under some conditions such as supplementation with a {gamma}-aminobutyric acidA agonist (16–18). From our present findings, the inhibitory effects of these IV anesthetics on SPR function may be one of the mechanisms of their antinociceptive effects at the spinal level. Tramadol and propofol have antinociceptive effects (19,20); however, these compounds had no effects of SPR function in our present study. SPR would have little relationship with mechanisms of analgesic effects of propofol or tramadol.

Our study raises the question of how ketamine and pentobarbital inhibit SPR function. There is considerable evidence that PKC plays an important role in the regulation of G protein-coupled receptors. We reported that the inhibitory effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on the SP-induced Ca2+-activated Cl- currents in Xenopus oocytes expressing SPR were blocked by pretreatment with PKC inhibitors, results which suggest that these anesthetics and ethanol inhibit SPR function via activation of PKC (6). However, the PKC inhibitor (GF109203X) did not abolish the inhibitory effects of ketamine and pentobarbital on SPR function in the present study, suggesting that these IV anesthetics inhibit SPR function by mechanisms other than the PKC pathway. Moreover, ketamine and pentobarbital had few effects on AlF4--induced currents, suggesting that ketamine and pentobarbital may not interfere with the signaling pathways downstream of activation of G proteins, such as phospholipase C activation, intracellular Ca2+ release, and Ca2+-activated Cl- channels. Ketamine and pentobarbital have no effects on the function of 5-hydroxytryptamine2A receptors, although they share the same signaling as SPR (21). From our present and previous results, it is likely that ketamine and pentobarbital inhibit the SP-induced Cl- currents possibly because of direct interaction with SPR.

To confirm this hypothesis, we examined the effects of ketamine and pentobarbital on [3H]-SP binding to SPR expressed in Xenopus oocytes. Ketamine and pentobarbital inhibited the specific binding of [3H]-SP to the SPR. Scatchard plot analysis of the [3H]-SP binding revealed that ketamine and pentobarbital decreased the Bmax and Kd values in a noncompetitive manner. These findings suggest that ketamine and pentobarbital would inhibit the function of SPR by interacting with the binding of SP, but the sites of ketamine and pentobarbital would be different from the SP-binding site on the SPR. However, volatile anesthetics such as halothane disrupt receptor-mediated signal transduction by interference with receptor-G protein interactions (22). Ishizawa et al. (23), on the contrary, reported that G protein-coupled receptors are direct targets of inhaled anesthetics including halothane. Do ketamine and pentobarbital directly inhibit receptor-G protein interactions or SPR? To answer this question, it is required to investigate the region of SPR responsible for ketamine and pentobarbital action using chimeric SPR between SPR and 5-hydroxytryptamine2A receptors or site-directed mutagenesis of SPR.

In conclusion, our results suggest that ketamine and pentobarbital, but not propofol and tramadol, inhibit SPR function. This finding suggests that the inhibition of SPR function by these compounds may be important in the analgesic effects of these IV anesthetics. However, it was reported that SP does not mediate acute pain sensation (5). Therefore, to establish a primary role of SPR modulation as a significant mechanism for analgesic effects of either ketamine or pentobarbital, more definitive studies, such as the use of the SPR knockout mouse model, would be required.


   Acknowledgments
 
Supported, in part, by Grants-in-Aid (Nos. 12770851, 12671515, 12671516, 12877248, 13671626, 14571479, 14704040, and 14657399) from the Ministry of Education, Science, and Culture of Japan, by a UOEH Research Grant for Promotion of Occupational Health, by Uehara Memorial Foundation, and by the Kanehara-Ichiro Memorial Medical Foundation.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Accepted for publication February 25, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press