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Anesth Analg 2007;104:1434-1439
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000261509.72234.a6

ANESTHETIC PHARMACOLOGY

The Effects of the Local Anesthetics Lidocaine and Procaine on Glycine and {gamma}-Aminobutyric Acid Receptors Expressed in Xenopus Oocytes

Koji Hara, MD, PhD, and Takeyoshi Sata, MD, PhD

From the Department of Anesthesiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.

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


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The voltage-dependent sodium channel is the primary site of action for local anesthetics (LAs). Although systemically administered low-dose LAs have been shown to exert antihyperalgesic effects, the molecular targets responsible for these effects are not fully known and their functional effects on inhibitory neurotransmitter receptors associated with antinociception have not been sufficiently studied.

METHODS: We examined the effects of lidocaine and procaine (0.1 µM to 3 or 10 mM) on recombinant human {alpha}1 glycine, {alpha}1β2{gamma}2S {gamma}-aminobutyric acid type A (GABAA), and {rho}1 GABAC receptors expressed in Xenopus laevis oocytes, using a two-electrode voltage-clamp system. We also evaluated the effects of LAs on two mutant glycine receptors, {alpha}1(S267C) and {alpha}1(S267Q), in an effort to clarify the interaction between LAs and glycine receptors.

RESULTS: Low concentrations of both lidocaine and procaine enhanced glycine receptor function, whereas high concentrations of lidocaine and procaine inhibited glycine receptor function. Lidocaine (10 µM) produced a significant leftward shift in the glycine concentration-response curve, indicating an increase in the apparent affinity for glycine. This enhancement was not altered in the mutant receptors. Both lidocaine and procaine at high concentrations inhibited GABAA receptor currents, whereas neither lidocaine nor procaine affected GABAC receptor function.

CONCLUSIONS: Lidocaine and procaine enhanced glycine receptor function at low concentrations and inhibited the functions of glycine and GABAA receptors at high concentrations. The mechanism of the LA-induced enhancement of glycine receptor function probably differs from that of general anesthetics. These findings may explain the pharmacological effects of LAs, such as antinociception and convulsion.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The voltage-dependent sodium channel is believed to be the primary target for local anesthetics (LAs). LAs also have several other pharmacological actions, such as blocking of calcium and potassium channels (1,2) and inhibition of N-methyl-d-aspartate receptors (3). Previous studies have shown antihyperalgesic effects of systemically administered LAs; in particular, low-dose lidocaine and procaine suppressed hyperalgesia in the central nervous system (4–6).

Inhibitory synaptic transmission in the spinal cord plays a pivotal role in suppressing the development of hyperalgesia and allodynia. Glycine receptors are distributed primarily in the spinal cord, with glycinergic neurons comprising the major inhibitory neurotransmitter system in the spinal cord and brainstem. Intrathecal administration of the glycine receptor antagonist strychnine induces allodynia or hyperalgesia (7). It has also been reported that {gamma}-aminobutyric acid type A (GABAA) receptor antagonists induce hyperalgesia and allodynia, with GABAA agonists producing the opposite effects (8,9). One report indicated that GABAC receptors composed of {rho}1 subunits are also involved in modulating nociceptive neurotransmission in the spinal cord (10).

We hypothesized that the antihyperalgesic effects of LAs may be mediated by the modulation of glycine, GABAA, and/or GABAC receptor functions in the spinal cord. To test this hypothesis, we assessed whether representative LAs, the aminoamide lidocaine and the aminoester procaine, can affect the function of human recombinant {alpha}1 glycine, {alpha}1β2{gamma}2S GABAA, and {rho}1 GABAC receptors expressed in Xenopus laevis oocytes. We also assessed the effects of LAs on two mutant glycine receptors to gain a better picture of the mechanisms by which glycine receptor function is positively modulated. The subunit compositions of the recombinant glycine and GABAA receptors were chosen in accordance with the predominant subunit distributions in the spinal cord.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study was approved by the Ethics Committee of Animal Care and Experimentation at the University of Occupational and Environmental Health, Japan. Xenopus female frogs were purchased from Seac Yoshitomi (Fukuoka, Japan). Lidocaine hydrochloride, procaine hydrochloride, glycine, and GABA were obtained from Sigma (St. Louis, MO). Human cDNAs encoding the {alpha}1 glycine receptor subunits (in pBK-CMV vector); the {alpha}1, β2, and {gamma}2S GABAA receptor subunits (in pBK-CMV, pCDM8, and pCIS2 vectors, respectively); and the {rho}1 GABAC receptor subunits (in pcDNA1 vector) were used for nuclear injections. The frogs were anesthetized in water with 3-aminobenzoic acid ethyl ester (240 mg/200 mL water) for all surgical procedures. The isolation of Xenopus oocytes was conducted as previously described (11). The isolated oocytes were placed in modified Barth’s saline (MBS), containing 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO3, 0.82 mM MgSO4, 0.91 mM CaCl2, 0.33 mM Ca(NO3)2, and 10 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES) adjusted to pH 7.5. The cDNA receptor subunits for {alpha}1 glycine (1 ng/30 nL), for {alpha}1, β2, and {gamma}2S GABAA (2 ng/30 nL in a 1:1:2 molar ratio), or for {rho}1 GABAC (1.5 ng/30 nL) were injected into the animal poles of oocytes by a blind method (12).

Each injected oocyte was placed individually in a well of a tissue culture plate (Corning Glass Works, Corning, NY) containing sterile MBS incubation medium supplemented with 10 mg/L of streptomycin, 100,000 U/L of penicillin, 50 mg/L of gentamycin, 90 mg/L of theophylline, and 220 mg/L of pyruvate, and incubated at 15°C-19°C. Oocytes were used for electrophysiological recordings at 2-5 days postinjection, as previously described (13).

The oocytes expressing recombinant receptors were placed in a rectangular chamber (volume, approximately 100 µL) and perfused with MBS at 2 mL/min. The animal pole of an oocyte was impaled with two glass electrodes (0.5-10 M{Omega}) filled with 3 M KCl, and the oocyte was voltage clamped at -70 mV using a model OC-752B oocyte clamp (Warner Instruments, Hamden, CT). Glycine or GABA was dissolved in MBS and applied for 20 s to oocytes expressing glycine or GABAA receptors, respectively. For oocytes expressing GABAC receptors, GABA was dissolved in MBS and applied for 2 min. When testing the effects of lidocaine and procaine (0.1 µM to 3 or 10 mM), the experiments were performed at the EC5 of glycine and GABA for the glycine and GABAA receptors, and at the EC10 of GABA for the GABAC receptor, as previously reported (14). To obtain a control response, agonists were repeatedly applied to the oocyte until a consistent response was observed. The LAs were dissolved in MBS and preapplied for 1 min before being coapplied with glycine or GABA. There was a 10-min washout period between drug applications. The effects of the LAs were expressed as a percentage of the control response. To address the mechanism of lidocaine’s action on the {alpha}1 glycine receptor, we further examined the influences of lidocaine (10 µM and 3 mM) on the glycine concentration-response relationship (10 µM to 1 mM).

Previous studies have indicated that serine267, located between transmembrane Domains 2 and 3 of the glycine {alpha}1 subunit, is critical for the positive modulation of receptor function by anesthetics and ethanol (15–17). Accordingly, we tested the effect of the LAs on the homomeric {alpha}1(S267x) mutant glycine receptor in which serine267 had been substituted with cysteine (C) or glutamine (Q), to help clarify the mechanism of the positive modulation of glycine receptors by lower LA concentrations. The mutated glycine {alpha}1(S267x) subunits were constructed using site-directed mutagenesis as described previously (15).

Data were obtained from five to eight oocytes taken from at least three different frogs. The EC50, the Hill coefficient, and the half-maximal inhibition concentration (IC50) values were calculated by fitting the data to a sigmoidal dose-response (variable slope) equation using GraphPad Prism 3.02 software (GraphPad, San Diego, CA). Data are represented as mean ± sem. Statistical analyses were performed using one-way analysis of variance by a Dunnett t-test for multiple comparisons in Figures 1–3, by unpaired Student’s t-test for comparisons of the values of EC50 and IC50 between control and lidocaine in Figure 4, and by paired Student’s t-test for comparisons of the currents at each concentration in Figure 4B. Differences were considered statistically significant at P < 0.05. All experiments were performed at room temperature (23°C).


Figure 120
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  		Figure 1. Effects of local anesthetics (LAs) on glycine receptors. (A) Representative current tracings in Xenopus oocytes. Oocytes expressing recombinant {alpha}1 glycine receptors were treated with glycine for 20 s. Lidocaine or procaine (10 µM and 3 mM) was preapplied for 1 min before being co-applied with glycine for 20 s. Bars represent the duration of application. (B) Effects of different concentrations (0.1 µM-10 mM) of LAs. Lidocaine and procaine enhanced the currents at lower concentrations. On the other hand, lidocaine and procaine inhibited glycine currents at high concentrations. Data are represented as mean ± sem n = 5 or 6 oocytes. Asterisks indicate statistical significance (P < 0.05).

 

Figure 420
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  		Figure 4. Effects of lidocaine on the agonist concentration-response relationship for {alpha}1 glycine receptors. (A) Lidocaine (10 µM) significantly shifted the glycine concentration-response curve to the left, indicating an increase in the apparent affinity for the agonist. (B) Lidocaine (3 mM) significantly inhibited the glycine concentration-response curve without altering the EC50 or Hill coefficient, indicating noncompetitive inhibition. Error bars represent sem. n = 5 to 8 oocytes. Asterisks indicate statistical significance (P < 0.05).

 


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  		Figure 2. Effects of local anesthetics (LAs) on {gamma}-aminobutyric acid type A (GABAA) receptors. (A) Representative current tracings in Xenopus oocytes. Oocytes expressing recombinant {alpha}1β2{gamma}2S GABAA receptors were treated with GABA for 20 s. Lidocaine or procaine (10 µM and 3 mM) was pre-applied for 1 min before being co-applied with GABA for 20 s. Bars represent the duration of application. (B) Effects of different concentrations (0.1 µM-3 mM) of the LAs. Lidocaine and procaine inhibited GABAA currents at high concentrations. Data are represented as mean ± sem n = 5 or 6 oocytes. Asterisks indicate statistical significance (P < 0.05).

 


Figure 320
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  		Figure 3. Effects of local anesthetics (LAs) on {gamma}-aminobutyric acid type C (GABAC) receptors. (A) Representative current tracings in Xenopus oocytes. Oocytes expressing recombinant {rho}1 GABAC receptors were treated with GABA for 2 min. Lidocaine or procaine (3 mM) was pre-applied for 1 min before being co-applied with GABA for 2 min. Bars represent the duration of application. (B) Effects of different concentrations (0.1 µM-3 mM) of the LAs. Neither lidocaine nor procaine affected the currents, even at the highest concentration. Data are represented as mean ± sem n = 6 to 8 oocytes.

 


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Consistent with previous reports on recombinant {alpha}1 glycine, {alpha}1β2{gamma}2S GABAA, and {rho}1 GABAC receptors, outward chloride currents were observed in response to the application of agonists to the oocytes (Figs. 1–3A). The control currents for the glycine, GABAA, and GABAC receptors in response to the EC5 or EC10 of agonists were 640 ± 60, 580 ± 70, and 140 ± 30 nA, respectively.

Lidocaine and procaine enhanced wild-type glycine receptor function at lower concentrations, with peak currents observed at 10 µM (lidocaine, 100% ± 16%; procaine, 92% ± 12%, P < 0.01). At higher concentrations, lidocaine and procaine inhibited the glycine receptor (at 10 mM: lidocaine, –70% ± 4%; procaine –34% ± 3%; Fig. 1B). Both lidocaine and procaine also inhibited GABAA receptor function at high concentrations (at 3 mM: lidocaine, –29% ± 4%; procaine –65% ± 4%; Fig. 2B). Procaine appeared to have a more potent inhibitory effect than lidocaine, consistent with extant literature (18). The GABAC receptor was not affected by the LAs at concentrations up to 3 mM (Fig. 3B). Lidocaine (10 µM) shifted the glycine concentration-response curve leftward, as has been reported for general anesthetics (11), indicating an increase in the apparent affinity for the agonist (Fig. 4A). Nonlinear regression analysis of the concentration-response curves yielded EC50 values for glycine of 130 ± 6 µM under control conditions and 85 ± 5 µM with lidocaine (P < 0.01). The Hill coefficients for the control and lidocaine conditions were 1.7 ± 0.2 and 1.8 ± 0.1, respectively. Preliminary experiments showed that procaine (10 µM) also shifted the glycine concentration-response curve leftward to a similar extent to lidocaine (10 µM) (data not presented). Higher concentrations of lidocaine (3 mM) shifted the glycine concentration-response curve downwards (P < 0.01) without changing the EC50 or Hill coefficient (control: EC50, 125 ± 8 µM; Hill coefficient, 1.8 ± 0.2; lidocaine: EC50, 131 ± 4 µM; Hill coefficient, 1.7 ± 0.2), indicating noncompetitive inhibition (Fig. 4B).

The facilitatory effects of the LAs (10 µM) were not altered in either mutant glycine {alpha}1(S267x) receptors; the LA-induced enhancement of the glycine currents in the two mutants was similar to that in wild-type receptors (Fig. 5). In the {alpha}1(S267C) glycine receptor, lidocaine and procaine enhanced the currents by 77% ± 8% and 66% ± 10%, respectively. In the {alpha}1(S267Q) glycine receptor, lidocaine and procaine enhanced the currents by 72% ± 8% and 79% ± 14%, respectively. These results indicate that LAs do not interact with the putative binding pocket containing serine267, as do various general anesthetics (15–17).


Figure 520
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  		Figure 5. Effects of local anesthetics on homomeric {alpha}1(S267x) mutated glycine receptors. Serine267 was substituted with cysteine (C) or glutamine (Q). Lidocaine and procaine enhanced the glycine-induced currents in both {alpha}1(S267C) and {alpha}1(S267Q) receptors in a manner similar to that in wild-type receptors. Error bars represent sem. n = 5 oocytes.

 

Neither lidocaine nor procaine influenced the baseline currents of wild-type or mutant glycine, GABAA, or GABAC receptors.


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Here we report that the LAs lidocaine and procaine can modulate glycine and GABAA receptors expressed in Xenopus oocytes. In humans, toxicity is observed at plasma lidocaine concentrations more than 4 µg/mL (19) corresponding to approximately 17 µM. Thus, lidocaine concentrations of 10 µM or less could be regarded as clinically relevant. In this study, the peak enhancement of the glycine receptor was observed at the LA concentration of 10 µM. This is considerably lower than the LA concentration needed to inhibit voltage-gated sodium channels. The IC50 value of lidocaine for voltage-dependent sodium currents was 112 µM in rat dorsal horn neurons (20) and 42 µM in dorsal root ganglion neurons (21). For sodium channels in sciatic nerve fibers of Xenopus laevis, the IC50 values were 204 µM for lidocaine and 60 µM for procaine (22). The relatively potent effects of LAs seen here suggest that glycine receptors represent a plausible target for LAs.

Glycine receptors are the predominant inhibitory receptors in the spinal cord. Intrathecal administration of strychnine, an antagonist of the glycine receptor, has been shown to induce allodynia or hyperalgesia (7). Interestingly, we demonstrated that the lidocaine modulation of {alpha}1 glycine receptors was biphasic, with facilitation at lower concentrations and inhibition at concentrations larger than 1 mM. This suggests the presence of two lidocaine binding sites, with the higher affinity site accounting for enhancement. Lidocaine at lower concentrations shifted the glycine concentration-response curve leftward, indicating that the enhancement produced by a given lidocaine concentration decreased with increasing glycine concentration. Given that physiological glycine concentrations at the synaptic cleft are much higher than those used in this study, the enhancing effects of lidocaine may be of limited relevance in vivo. The high concentration of lidocaine inhibited the glycine concentration-response curve in a noncompetitive manner. This indicates that lidocaine seems to interact with the allosteric modulatory site on the receptor rather than its glycine recognition site. Glycine receptors are well established as playing an important role in controlling motor functions as well as inhibitory sensory modulation. It would be interesting to see, in further experiments, the different effects on the glycine receptor between bupivacaine and etidocaine, which seem to differ so greatly in their motor effects clinically.

Various anesthetics can enhance the function of glycine receptors. This is thought to occur via their binding to a pocket formed between transmembrane domains 2 and 3 (15–17). We made two mutated glycine receptors in which serine267 (residue volume, 53 Å3), a critical residue in this pocket, was substituted with a larger neutral amino acid, cysteine (65 Å3) or glutamine (86 Å3). Previous studies have shown that this small change in volume can abolish the enhancement by anesthetics (11,16,17). In the present study, lidocaine still enhanced both mutant receptors. These results suggest that the site of action of LA-induced positive modulation is distinct from the site of action of general anesthetics at the glycine receptor. Additional experiments are needed to understand the precise locations and compositions of these two binding sites and the mechanisms underlying the biphasic actions of lidocaine.

GABAergic neurons mediate presynaptic inhibition in the spinal cord and regulate nociceptive neurotransmission. GABAA receptors were not affected by the LAs at clinically relevant concentrations but were inhibited at high LA concentrations (>300 µM). The inhibition of GABAergic neurons leads to convulsion. Thus, these finding are consistent with the clinical observation that systemic administration of LAs does not affect consciousness, whereas high toxic doses of LAs induce convulsion. The clinical significance of the weak inhibition of GABAA receptors at high LA concentrations is still somewhat unclear. However, this inhibition might decrease convulsive thresholds and lead to convulsion, especially when other proconvulsive conditions are present.

Of relevance to the present study, Supplisson and Chesnoy-Marchais (23) showed that tropisetron, an antagonist of the 5-hydroxytryptamine3 receptor (one of a superfamily of ligand-gated ion channels that includes the glycine and GABA receptors), had a concentration-response curve and the biphasic profile, with an initial enhancement followed by inhibition similar to those of lidocaine in homomeric {alpha}1 glycine receptors expressed in Xenopus oocytes. Supplisson and Chesnoy-Marchais (23) also demonstrated that heteromeric glycine receptors expressed with both β and {alpha}1 subunits were only enhanced and not inhibited, whereas the converse was true for homomeric {alpha}2 glycine receptors. They suggested that the modulation of the glycine receptor by tropisetron markedly depended on the receptor subunit composition.

A previous study by Hara et al. (24) showed that high concentrations of lidocaine inhibited glycine- and GABA-evoked chloride currents in dissociated rat hippocampal neurons. They demonstrated that high concentrations (1-10 mM) of lidocaine inhibited glycine- and GABA-evoked currents in a concentration-dependent manner. However, they could not find the enhancing effects of LAs at low concentrations (personal communication to Professor Yoshimi Ikemoto, Faculty of Dental Science, Department of Dental Anesthesiology, Kyushu University). The reason for the discrepancy regarding the enhancement by low concentrations of LAs is not clear, but the differences may be attributable to differences in species, tissue preparation, receptor subunit composition, or experimental conditions (temperature, pH, and glycine concentration). In addition, they showed that the neutral form of LA was more potent than the charged form regarding the inhibitory effects at high concentrations. To examine the difference in the enhancing potency at low concentrations between the neutral and the charged form would give us a hint for resolving the interactive mechanism (extra- or intracellular) between LAs and glycine receptors. An earlier study investigating the effects of lidocaine and procaine on murine GABAA receptor subunits expressed in Xenopus oocytes (18) showed that both lidocaine and procaine inhibited receptor function to an extent similar to that found in our study. The inhibitory potency of procaine was higher than that of lidocaine, which is compatible with our findings.

One report (10) demonstrated that transgenic mice lacking GABA {rho}1 subunits exhibited hyperalgesia, suggesting that the GABAC receptor plays an important role in modulating nociceptive neurotransmission in the spinal cord. However, the present results indicate that it is unlikely the GABAC receptor is involved in the pharmacological effects of lidocaine and procaine.

In summary, the present study examined the effects of two LAs on ligand-gated ion channels involved in inhibitory neurotransmission related to nociception in the spinal cord. Although the clinical significance of the biphasic modulation of the glycine receptor by lidocaine and the enhancement by procaine in this study remains to be determined, the LA-mediated enhancement of glycine receptors and inhibition of GABAA receptors may contribute to the reduction in allodynia and hyperalgesia and to the proconvulsive effect observed at high LA concentrations.


   ACKNOWLEDGMENTS
 
We thank Dr. Paul J Whiting for kindly providing GABAA receptor subunits cDNAs, Dr. George R. Uhl for GABAC receptor subunit cDNA and Dr. Heinrich Betz for glycine receptor subunit cDNA. We also thank Dr. James R. Trudell for calculating molecular volumes and Dr. R. Adron Harris for great attention to this study.


   Footnotes
 
Supported by Grants-in-Aid for Research from the Ministry of Education, Science and Culture of Japan, No. 17791059.

Accepted for publication February 14, 2007.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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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 2007 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press