Anesth Analg 2002;94:79-83
© 2002 International Anesthesia Research Society
ANESTHETIC PHARMACOLOGY
The Inhibitory Effects of Anesthetics and Ethanol on Substance P Receptors Expressed in Xenopus Oocytes
Kouichiro Minami, MD PhD*,
Munehiro Shiraishi, MD*,
Yasuhito Uezono, MD PhD
,
Susumu Ueno, MD PhD
, and
Akio Shigematsu, MD PhD*
Departments of *Anesthesiology and Pharmacology, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan; and Second Department of Pharmacology, Nagasaki University School of Medicine, Nagasaki, Japan
Address correspondence and reprint requests to Kouichiro Minami, MD, PhD, Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, Fukuoka 807-8555, Japan. Address e-mail to kminami{at}med.uoeh-u.ac.jp
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Abstract
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The neuropeptide substance P (SP) modulates nociceptive transmission within the spinal cord. SP is unique to a subpopulation of C fibers found within primary afferent nerves. However, the effects of anesthetics on the SP receptor (SPR) are not clear. In this study, we investigated the effects of volatile anesthetics and ethanol on SPR expressed in Xenopus oocytes. We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents mediated by SPR expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the volatile anesthetics tested, and ethanol, inhibited SPR-induced Ca2+-activated Cl- currents at pharmacologically relevant concentrations. The protein kinase C inhibitor bisindolylmaleimide I (bisindolylmaleimide) enhanced the SP-induced Cl- currents. However, bisindolylmaleimide abolished the inhibitory effects on SPR of the volatile anesthetics examined and of ethanol. These results demonstrate that halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit the function of SPR and suggest that activation of protein kinase C is involved in the mechanism of action of anesthetics and ethanol on the inhibitory effects of SPR.
IMPLICATIONS: We examined the effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on substance P receptor (SPR) expressed in Xenopus oocytes, by using a whole-cell voltage clamp. All the anesthetics and ethanol inhibited SPR function, and the protein kinase C (PKC) inhibitor abolished these inhibitions. These results suggest that anesthetics and ethanol inhibit SPR function via PKC.
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Introduction
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The neuropeptide substance P (SP) receptors (SPRs) belong to the family of G-protein-coupled receptors and are widely distributed in the central nervous system and in peripheral nerves. SP acts as a neurotransmitter released from C fibers found within nociceptive primary afferent neurons into the spinal cord and mediates part of the excitatory synaptic input to nociceptive neurons at this level (1–3). A study in mice lacking the gene encoding SPR showed that the mice had altered pain sensitivity. A reduction in nociceptive responses to certain somatic and visceral noxious stimuli occurs in SPR knockout mice (4–6). Although it has been believed that G-protein-coupled receptors are one of the targets of some anesthetics and ethanol in the nervous system (7), the effects of anesthetics and ethanol on SPR have not been studied.
The Xenopus oocyte expression system has been widely used to study a multiplicity of brain receptors with pharmacological properties that mimic those of native brain receptors (8). Stimulation of SPR results in activation of Ca2+-activated Cl- currents in Xenopus oocytes (9); SPR stimulation leads to G-protein-dependent activation of phospholipase C, resulting in the formation of inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate 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 anesthetics and ethanol on G-protein-coupled receptors; it was therefore used for this study.
We investigated the effects of the volatile anesthetics halothane, enflurane, isoflurane, and diethyl ether, and those of ethanol, on SP-induced Cl- currents in Xenopus oocytes expressing SPR. We also examined the effects of these compounds in the absence or presence of a selective protein kinase C (PKC) inhibitor, to delineate the mechanisms by which these compounds alter the function of SPR.
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Methods
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Adult Xenopus laevis female frogs were purchased from Seac Yoshitomi (Yoshitomi, Fukuoka, Japan); SP was from Sigma (St. Louis, MO); ethanol, diethyl ether, and dimethyl sulfoxide were from Nacalai Tesque (Kyoto, Japan); halothane, isoflurane, and enflurane were from Dinabot Laboratories (Osaka, Japan); bisindolylmaleimide I (bisindolylmaleimide) 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 complementary DNA (cDNA). 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 mRNA Capping Kit and was 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. (10). Briefly, Xenopus oocytes were injected with 50 ng of cRNA encoding SPR. Oocytes were placed in a 100-µL recording chamber and perfused with modified Barth’s saline containing 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO3, 10 mM HEPES, 0.82 mM MgSO4, 0.33 mM Ca(NO3)2, and 0.91 mM CaCl2 (pH 7.5) at a rate of 1.8 mL/min at room temperature. Recording and clamping electrodes (1–5 M
) were pulled from 1.2-mm-outside-diameter capillary tubing and filled with 3 M KCl. A recording electrode was embedded 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. (11). The volatile anesthetics (halothane, isoflurane, enflurane, and diethyl ether) and ethanol were preapplied for 2 min to allow for complete equilibration in the bath. The solutions of volatiles were freshly prepared immediately before use. The concentrations in the figures represent the bath concentrations. We calculated the final concentration of the volatile compounds in the recording chamber as reported previously (12).
To determine whether activation of PKC plays a role in anesthetic and ethanol modulation of SPR-mediated events, oocytes were exposed to bisindolylmaleimide I (bisindolylmaleimide) (200 nM) (13) in modified Barth’s saline for 20–120 min. SP was applied at 20, 40, 60, and 120 min during the bisindolylmaleimide treatment. SP was simultaneously applied in oocytes without bisindolylmaleimide treatment as a control.
The results are expressed as percentages of control responses caused by the variable SPR expression in oocytes. The control responses were measured before and after each drug application to take into account possible shifts in the control currents as recording proceeded. In the experiments testing the effects of bisindolylmaleimide, however, we used the SP-induced currents before bisindolylmaleimide application as a control, because the effects of these drugs are not readily reversible. The n values refer to the number of oocytes studied. Each experiment was conducted with oocytes from at least two different frogs. Statistical analyses were performed by using either a Student’s t-test or a one-way analysis of variance. Curve fitting and estimation of 50% inhibitory concentration values for concentration-response curves were performed with GraphPad Inplot software (San Diego, CA).
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Results
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Anesthetic modulation of receptor function often depends on the degree of receptor activation (8), and it was necessary to determine the SP concentration-response relationship under our experimental conditions before testing the anesthetics (Fig. 1). Nonlinear regression analysis of these curves yielded a 50% effective concentration for SP of 150 ± 49 nM and a Hill coefficient of 1.3 ± 0.2. Maximal currents were observed at 10 µM (Fig. 1). On the basis of the results in Figure 1, the effects of anesthetics and ethanol on SP-induced currents were examined at an SP concentration of 100 nM. Halothane, enflurane, isoflurane, diethyl ether, and ethanol all inhibited the Cl- currents activated by SP (Figs. 2 and 3). Halothane inhibited the action of 100 nM SP to 77.1% ± 6.6%, 64.3% ± 6.4%, and 41.6% ± 9.9% of the control at 0.25, 1, and 2 mM, respectively. Enflurane inhibited the currents activated by SP to 90.3% ± 12.6%, 73.6% ± 5.9%, and 55.6% ± 9.3% of the control at 0.25, 1, and 2 mM, respectively. Isoflurane inhibited the currents activated by SP to 61.5% ± 7.2%, 29.5% ± 12.3%, and 31.3% ± 12.5% of the control at 0.3, 1, and 2 mM, respectively. Diethyl ether inhibited the currents activated by SP to 91.6% ± 13.9%, 77.7% ± 4.9%, and 65.3% ± 10.6% of the control at 3, 9.3, and 18.6 mM, respectively. Ethanol inhibited the currents activated by SP to 77.5% ± 14.6%, 73.8% ± 7.7%, and 54.6% ± 5.3% of the control at 50, 100, and 200 mM, respectively.
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Figure 1. Concentration-response curve for substance P (SP) (1 nM to 10 µM) activation of a Ca2+-activated Cl- current in Xenopus oocytes expressing SP receptor. Oocytes were voltage-clamped at -70 mV. SP was applied for 20 s, and the peak current was measured. Values are the mean ± SEM for 10 oocytes. In some cases, the error bars are smaller than the symbols.
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Figure 2. Effects of varying concentrations of volatile anesthetics (halothane [Hal.], isoflurane [Iso.], enflurane [Enf.], and diethyl ether) and ethanol on the Cl- currents evoked by 100 nM substance P (SP) in oocytes expressing SP receptor. Halothane (0.25–2 mM), isoflurane (0.3–2 mM), enflurane (0.3–2 mM) (A), diethyl ether (1–19 mM) (B), and ethanol (12.5–200 mM) (C) were preapplied for 2 min before being coapplied with SP for 20 s. Data represent the mean ± SEM for 10–13 oocytes.
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Figure 3. (A) Typical tracings were obtained from a single oocyte and show the effects of halothane (Hal.), isoflurane (Iso.), enflurane (Enf.), diethyl ether (Ether), and ethanol (EtOH) (Con. = control) at concentrations corresponding to the minimum alveolar anesthetic concentration (MAC) for Cl- currents evoked by 100 nM substance P (SP) in oocytes expressing SP receptor (SPR). The concentrations used were as follows (mM): halothane (0.25), isoflurane (0.3), enflurane (0.5), diethyl ether (9.5), and ethanol (190). (B) Effects of several volatile anesthetics and ethanol at concentrations corresponding to MAC for Cl- currents evoked by 100 nM SP in oocytes expressing SPR. The concentrations used were as follows (mM): halothane (0.25), isoflurane (0.3), enflurane (0.5), diethyl ether (9.5), and ethanol (190). Data represent the mean ± SEM of five oocytes.
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We next investigated whether the inhibitory effects of halothane, enflurane, isoflurane, diethyl ether, and ethanol on SP-induced currents could be modulated by PKC. These compounds were studied by using Xenopus oocytes that were pretreated with the PKC inhibitor bisindolylmaleimide (200 nM), which has a Ki value for inhibiting PKC activity of 20 nM (13). Treatment with bisindolylmaleimide produced a 1.6-fold enhancement of the initial Cl- currents activated by 100 nM SP (Fig. 4A). However, the inhibitory effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents were not observed in the oocytes pretreated with bisindolylmaleimide (Fig. 4B).
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Figure 4. (A) Effects of bisindolylmaleimide I on substance P (SP)-induced Cl- current in oocytes expressing SP receptor. Oocytes were incubated with bisindolylmaleimide (200 nM) for 120 min. SP (100 nM) was applied at 5, 20, 40, 60, and 120 min during treatment of bisindolylmaleimide ( ). SP was also applied at the same intervals in oocytes incubated without bisindolylmaleimide, as a control ( ). Data represent the mean ± SEM for 10 oocytes. (B) Comparison of the effects of the protein kinase C inhibitor (PKCI) bisindolylmaleimide on the inhibitory effects of halothane (Hal.), isoflurane (Iso.), enflurane (Enf.), diethyl ether (Ether), or ethanol (EtOH) at concentrations corresponding to the minimum alveolar anesthetic concentration (MAC). Oocytes were incubated with 200 nM bisindolylmaleimide (PKCI) for 120 min. The volatile anesthetics and ethanol at the MAC concentrations shown were preapplied for 2 min before being coapplied with SP (100 nM) for 20 s. The control indicated the effects of anesthetics and ethanol before application of bisindolylmaleimide. The concentrations used were as follows (mM): halothane (0.25), isoflurane (0.3), enflurane (0.5), diethyl ether (9.5), and ethanol (190). Data represent the mean ± SEM for five separate determinations. A paired Student’s t-test was used for the statistical analysis. Significant action of bisindolylmaleimide is indicated by *P < 0.05 and **P < 0.01.
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Discussion
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Our results demonstrate that the volatile anesthetics halothane, enflurane, isoflurane, and diethyl ether, as well as ethanol, inhibit the function of SPR. The minimal alveolar anesthetic concentrations (MAC) are as follows (mM): halothane (0.25), isoflurane (0.3), enflurane (0.5), diethyl ether (9.5), and ethanol (190) (8,14). All the anesthetics and the ethanol used inhibited SPR function to 50% of the control at a concentration of approximately 2 MAC in our study, suggesting that these anesthetics and ethanol all inhibit SPR function at pharmacologically relevant concentrations. There have been some reports that showed that volatile anesthetics and ethanol inhibit the function of some G-protein-coupled receptors. Halothane inhibits the function of a muscarinic receptor expressed in Xenopus oocytes (11,15). Moreover, Minami et al. (16) reported the effects of anesthetics and ethanol on metabotropic glutamate receptors (mGluRs) that show little sequence homology with other metabotropic receptors. Ethanol and volatile anesthetics inhibit mGluR5 but do not affect the function of mGluR1 receptors, which use the same phosphatidylinositol signaling system as mGluR5 receptors. Our results are consistent with those of previous studies.
The pharmacological actions of general anesthetics include analgesia (17). Halothane, isoflurane, and enflurane depress the tail-flick response in mice; this is a standard method of estimating the depression of the response to noxious stimuli (18). Halothane, isoflurane, and diethyl ether were shown to significantly increase the hind paw withdrawal latency response to thermal nociceptive stimulation, suggesting that these anesthetics have analgesic properties (19). Gatch and Lal (20) examined the effects of acute and chronic administration of ethanol and of ethanol withdrawal on a radiant heat tail-flick assay of nociception in rats and showed that ethanol produces antinociception when administered acutely or chronically. This evidence suggests that halothane, isoflurane, enflurane, diethyl ether, and ethanol have antinociceptive effects. Our findings indicate that the inhibitory effects of these anesthetics and of ethanol are a mechanism of their antinociceptive effects.
The question of how these anesthetics inhibit SPR function arises. There is considerable evidence that PKC plays an important role in the regulation of G-protein-coupled receptors (10,11,16,21). We reported that halothane (1-chloro-1,2,2-trifluorocyclobutane), an F3 anesthetic, and ethanol inhibit the function of G-protein-coupled 5-hydroxytryptamine-2A receptors and M1 receptors via a PKC-sensitive pathway (11,21). Moreover, in vitro studies have demonstrated that halothane affects PKC activity in the brain (22–24). In addition, SPR is phosphorylated by PKC (25–27). Other investigators have suggested that ethanol also activates PKC activity in vivo by promoting its translocation from the cytosol to the membrane fraction (28,29). In these results, we showed that the inhibitory effects of halothane, isoflurane, enflurane, diethyl ether, and ethanol on SP-induced currents were blocked in oocytes treated with the PKC inhibitor, suggesting that these anesthetics and ethanol inhibit SPR function via activation of PKC. However, it should be noted that the effects of anesthetics and ethanol on PKC activity have not been measured in Xenopus oocytes, nor have the effects of anesthetics and ethanol been measured at the level of receptor protein phosphorylation. It is also of interest to determine whether mutation of phosphorylation sites in SPR abolishes the actions of anesthetics, as predicted by our hypothesis. Such studies are currently under way in our laboratory.
In conclusion, our results suggest that halothane, isoflurane, enflurane, diethyl ether, and ethanol inhibit SPR function by enhancing PKC activity. The finding suggests that the inhibition of SPR function by these compounds may be important in the analgesic effects of anesthetics.
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Acknowledgments
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This research was supported by Grants-in-Aid (11671532, 10770778, 12770851, 11770878, 12671515, 12671516, and 12770849) from the Ministry of Education, Science, and Culture of Japan, by a UOEH Research Grant for Promotion of Occupational Health, by the Japan Research Foundation for Clinical Pharmacology, by the Uehara Memorial Foundation, and by the Kanehara-Ichiro Memorial Medical Foundation.
We thank Dr. R. Adron Harris (Waggoner Center for Alcohol and Addiction Research, University of Texas, Austin) and Dr. Segawa (The Second Department of Internal Medicine, University of Occupational and Environmental Health School of Medicine, Kitakyushu, Japan) for kind discussion and technical suggestions.
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Footnotes
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Presented, in part, at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, 2000.
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Accepted for publication August 22, 2001.
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Abstract
Introduction
