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ANESTHETIC PHARMACOLOGY

Lidocaine and Octanol Have Different Modes of Action at Tetrodotoxin-Resistant Na⁺ Channels of Peripheral Nerves

Deniz Poyraz, MD^*, Michael E. Bräu, PD MD, Friederike Wotka, Cand Med^*, Birgit Puhlmann, MD^*, Andreas M. Scholz, PD MD, Prof. Gunter Hempelmann, MD, Prof. Wolfgang J. Kox, MD PhD^*, and Prof. Claudia D. Spies, MD^*

*Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité Campus Mitte, Humboldt University, Berlin, Germany; Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital, Justus-Liebig-University, Giessen, Germany; and Department of Physiology, Justus-Liebig-University, Giessen, Germany

Address correspondence and reprint requests to Claudia D. Spies, MD, Department of Anesthesiology and Intensive Care Medicine, University Hospital Charité Campus Mitte, Humboldt University, Schumannstr. 20/21, 10117 Berlin, Germany. Address e-mail to claudia.spies{at}charite.de

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Local anesthetics and alcohols block impulse conduction in peripheral nerves by inhibiting Na⁺ currents. In small peripheral nerve fibers, tetrodotoxin-resistant (TTX-r) Na⁺ channels play an important role in impulse generation. We investigated the effects of lidocaine and the alcohol octanol on TTX-r Na⁺ channels. Currents were recorded with the whole-cell patch-clamp method from enzymatically isolated rat dorsal root ganglion cells (data evaluation: nonlinear least-squares fitting). Lidocaine and octanol blocked the TTX-r Na⁺ current in a reversible and concentration-dependent manner (50% inhibitory concentration values: 177 ± 25 and 455 ± 25 µM, respectively). Lidocaine additionally produced a strong use-dependent block. Both drugs showed a strong dynamic block (i.e., block developed during the time course of current activation and inactivation). Double-pulse protocols showed a slow dissociation of lidocaine from the channel during repolarization (time constant: 1763 ± 63 ms; 300 µM). The dissociation of octanol was too quick to be distinguished from normal current repriming kinetics of 2.2 ms. Lidocaine and octanol acted noncompetitively in the Na⁺ channel. Lidocaine and octanol have different blocking properties on the TTX-r Na⁺ current and bind to different channel sites.

IMPLICATIONS: Lidocaine and octanol have different inhibitory effects on the function of tetrodotoxin-resistant Na⁺ channels in rat dorsal root ganglion cells, as well as noncompetitive modes of action, as investigated by the whole-cell patch-clamp method, and therefore are likely to have different binding sites on the channel.

	Introduction

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Alcohols have many effects on the nervous system. The molecular mechanisms are unclear, but the modulation of neuronal ion channels has been demonstrated (1). Alcohols alter nociception and may produce or interfere with anesthesia (1–3). An altered success rate for regional anesthesia and different dose requirements for local anesthetics have been reported in rats (4) and patients (5) consuming alcohol.

Molecular mechanisms accounting for anesthesia have been identified for local anesthetics, whereas less is known about alcohols. Neuronal Na⁺ currents are mediated by voltage-gated Na⁺ channels in the membranes of sensory neurons (6). They initiate action potentials and are responsible for impulse initiation and conduction in peripheral nerves (7). Both local anesthetics and alcohols block neuronal Na⁺ currents (6,8,9).

The Na⁺ channel isoforms Na_V1.8 (SNS/PN3) and Na_V1.9 (SNS2/NaN) in the sensory peripheral nervous system seem to play a key role in nociception and neuropathies (10). These channels are found mostly in small dorsal root ganglion (DRG) cells (11) associated with thin fibers (12) and show resistance to tetrodotoxin (TTX). TTX-resistant (TTX-r) channels have been cloned from rodent (11) and human (13) DRG cells.

Na⁺ channels are the main targets for local anesthetics; their putative binding site in the channel pore has been identified (14). For alcohols, no similar specific binding sites on Na⁺ channels have been detected.

In preliminary patch-clamp studies, we observed only a small effect on TTX-r Na⁺ channels with 1 to 30 mM ethanol, whereas at larger concentrations, cell damage occurred. We therefore chose the more lipophilic n-octanol, which suppresses Na⁺ currents at smaller concentrations (9). Our study was performed to gain further insight into the kinetic effects exerted by the alcohol octanol, as compared with the local anesthetic lidocaine, on TTX-r Na⁺ channels in rat DRG cells.

	Methods

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DRG cells were obtained from 12 male and female 6- to 8-wk-old Wistar rats, which had been killed by cervical dislocation under halothane anesthesia, according to the guidelines of the local veterinary authority. Permission of the local veterinary authority was given (No. G 0155/01).

Ganglia were prepared from the vertebral column and transferred into calcium- and magnesium-free Tyrode solution (see below). After connective tissue was removed, trypsin 1 mg/mL (Type I, 10,800 U/mL; Sigma, Deisenhofen, Germany) and collagenase 3 mg/mL (Type CLS II, 322 U/mg; Seromed, Berlin, Germany) were added to the solution. After 30 min at 37°C under gentle shaking, the ganglia were washed with the calcium- and magnesium-free Tyrode solution and incubated for 5 min with deoxyribonuclease 80 µg/mL (Type II/IV; Sigma) and trypsin-inhibiting enzyme 100 µg/mL (Type IS, Sigma) in plating medium at 22°C. The ganglia were then rinsed with calcium- and magnesium-containing Tyrode solution and were placed into fresh medium. Mechanical dissociation of the cells was performed with Pasteur pipettes with decreasing tip diameters.

Cells in the plating medium-containing culture dishes in an atmosphere of 95% oxygen and 5% CO₂ could be stored at 20°C–24°C for up to 4 days. Experiments were conducted after a 12-h resting period.

Glass capillaries (Type CEEBEE, 101-PS; Chr. Bardram, Svendborg, Denmark) were processed to pipettes by a micropuller (Type P-97; Sutter Instrument Co., Novato, CA). The tips were fire-polished before experiments and had a resistance of 0.9–2.8 M when filled with internal CsF solution.

Cells were transferred from the plating medium into a Petri dish containing external Tyrode solution, which was inserted into the stage of an inverted microscope (Zeiss, Jena, Germany). All investigations were performed as voltage-clamp experiments in the whole-cell configuration of the patch-clamp method (15).

Voltage stimuli were generated by a personal computer with pClamp 6.0 software (Axon Instruments, Burlingame, CA), and the currents were recorded by an Axopatch 200B amplifier (Axon Instruments). Data filtering was performed at 2 kHz before digitizing with a 12-bit analog/digital converter (Labmaster TM-40 AD/DA board; Scientific Solutions, Solon, OH) at 10 kHz.

Data were evaluated with pClamp 6.0 and Fig.P 6.0 software (Biosoft, Cambridge, UK). Capacitance and leakage current correction was performed on-line with the hardware of the patch-clamp amplifier.

The seal resistance of the cells ranged from 1 to 30 G, the series resistance compensation was 70%–80%, and the holding potential was set to -90 mV in each experiment. To perform complete solution exchange, cells were lifted up with the pipette and placed into the desired barrel of a multiple-barrel superfusion system, which had no effect on the stability of the gigaseal.

Calcium- and magnesium-free Tyrode solution contained the following (mM): NaCl 145, KCl 5, glucose 6, and HEPES 10. CaCl₂ 1 mM and MgCl₂ 1 mM was further added to the corresponding calcium- and magnesium-containing Tyrode solution. The pH was adjusted to 7.4 with Tris buffer [tris(hydroxymethyl)-aminomethane] (Merck, Darmstadt, Germany).

Plating medium was minimum essential medium containing 10% (vol/vol) fetal calf serum (Seromed), 4 mM L-glutamine, penicillin 100 IU/mL, and streptomycin 0.1 mg/mL. Medium and supplements were from Sigma.

External Tyrode solution (bath and control solution, dissolvent for the drugs) containing (mM) choline chloride 110, NaCl 35, KCl 5, CaCl₂ 1, MgCl₂ 1, glucose 6, HEPES 10, tetraethyl ammonium (TEA) chloride 10, and TTX 0.0001, pH (7.4), was corrected by Tris buffer.

Internal CsF solution contained (mM) CsF 140, NaCl 10, EGTA 3, and HEPES 10; pH was adjusted to 7.2 by adding CsOH. TEA inhibits K⁺ currents, and CsF inhibits K⁺ and Ca²⁺ currents.

For the stock solutions, lidocaine (0.1 M) was dissolved in doubly distilled water, and the hydrophobic octanol (1 M) was dissolved in dimethyl sulfoxide (DMSO). DMSO alone (0.253% vol/vol, corresponding to the DMSO content of the largest octanol concentration used) did not exert any effect on the investigated Na⁺ currents (data not shown).

n-Octanol, anesthetics, choline chloride, HEPES, and MgCl₂ were obtained from Sigma; KCl, CaCl₂, glucose, and TEA chloride were from Merck; NaCl was purchased from Roth (Karlsruhe, Germany); and TTX was from Latoxan (Valence, France). All fitting procedures were performed by nonlinear least-squares fitting.

Current-voltage relations were fitted with a modified Boltzmann function to evaluate reversal potential (E_rev) and half-maximal activation potentials (E_h,a):

where k_a is the steepness factor, I_Na is the Na⁺ current, G_Na,max is the maximal Na⁺ conductance, and E is the given test potential.

Inactivation or availability curves were fitted by a Boltzmann function:

where E_h,i is the half-maximal inactivation potential, k_i is the steepness factor, and I_Na,max is the maximal Na⁺ current.

The Hill equation was used to fit curves from concentration-inhibition relationships:

where h is the Hill coefficient, c is concentration, IC₅₀ is the half-maximal inhibition concentration, and f_i is the fractional block.

A biexponential function was used for fitting the normalized peak current data depending on recovery time after inactivation:

where ₁ and ₂ are time constants, a₁ and a₂ are fractional amounts of each exponential, t is time, and f_Na is the fractional Na⁺ current.

Competition experiments were performed with lidocaine and octanol to identify whether both drugs act at the same or different binding sites. For this, defined concentrations of octanol were applied to the cell, and the reduction in peak Na⁺ current amplitude was measured. Next, increasing concentrations of lidocaine were added to give concentration-inhibition relations for the octanol-preblocked currents, which were then fitted to Equation 3. If both drugs act at the same binding site, octanol will compete with lidocaine, resulting in an apparent shift of concentration dependence for the lidocaine block. The shift depends on the fractional reduction of the current by the previously applied octanol and can be calculated as follows:

where IC_50,app,lido is the apparent half-maximal blocking concentration for lidocaine in octanol, IC_50,lido is the half-maximal blocking concentration for lidocaine, and f_i,oct is the fractional block induced by octanol before the application of lidocaine. If both drugs act at independent sites, no shift of the IC₅₀ value for lidocaine will occur.

Depicted data points are mean values, and error bars represent SEM. Fitted values ± SE of the fit are given. Significance was tested by nonparametric analysis of variance (16) and was assumed for P < 0.05.

	Results

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Before each experiment, cell capacitance was measured by using the capacitance correction circuit of the patch-clamp amplifier. Assuming a specific membrane capacitance of 1 µF/cm² (17), cell surface can be estimated. Provided that the cells have a spherical shape, their diameter can then be calculated. The average capacitance (n = 63) was 29.9 ± 7.4 pF (mean ± SD), which corresponds to a diameter of 30.7 ± 3.8 µm (mean ± SD) and thus to small- and medium-sized cells.

Current-voltage relationships were evaluated from maximal current amplitudes evoked by 50-ms test potentials ranging from -80 to 60 mV, preceded by a 50-ms hyperpolarization to -110 mV. Fitting Equation 1 to each current-voltage relationship and averaging the variables revealed an E_rev of 27.9 ± 0.6 mV and an E_h,a of -26.8 ± 1.1 mV (n = 63).

Inactivation curves were constructed by plotting the peak Na⁺ current measured during a 10-ms depolarizing test pulse to -10 mV against the potential (-130 to 10 mV) of the 50-ms prepulse. Fitting Equation 2 to the data revealed an E_h,i of -34.0 ± 0.6 mV (n = 63).

Neither lidocaine (n = 5, 0.1 mM; n = 5, 0.3 mM) nor octanol (n = 5, 0.55 mM, 1.0 mM; n = 8, 0.3 mM) influenced E_rev. However, both substances increased E_h,a to more positive potentials and shifted E_h,i in the hyperpolarizing direction (Table 1).

View larger version (27K): [in this window] [in a new window]   Figure 1. A, Recordings of sodium currents from tetrodotoxin-resistant Na+ channels in rat dorsal root ganglion cells. Sodium currents were evoked by a 50-ms depolarizing potential step to 0 mV after a 50-ms hyperpolarization to -110 mV; the protocol (see inset, top) was repeated 10 times with a frequency of 2 Hz. Holding potential was -90 mV in all experiments. Dashed lines show the trace from the first pulse in control; continuous lines indicate the 10 successive traces in lidocaine (100 µM) and octanol (300 µM). B, Peak currents depending on the pulse number. Peak current is plotted against pulse number of the 10 successive traces in control, in octanol (300 and 550 µM; n = 13), and in lidocaine (100 and 300 µM; n = 7) normalized to the amplitude of the first trace in control and in each concentration. C, Concentration-inhibition relationship of lidocaine and octanol. Fractional tonic block (solid circles and solid line) and fractional use-dependent block (10th pulse at 2 Hz; open triangles; dashed line) of the Na+ inward peak current are plotted against blocker concentration. Data points are mean values, and error bars give SEM. Solid and dashed lines represent fits of a Hill function to the data points. The Hill coefficient was fixed to 1 when fitting the lidocaine data but was allowed to run free for the octanol data. For comparison, the dotted line shows the fit for octanol with a Hill coefficient fixed to 1. Half-maximal blocking concentrations and the Hill coefficient for octanol are given in Table 2.

From the original traces in the control and drug solutions, it is apparent that, besides a reduction in current amplitude, both lidocaine and octanol accelerate the inactivation time course. Time constants () (ms; ±SEM) were obtained from single exponential functions fitted to the data points of the curves’ inactivation part (Table 3).

View this table: [in this window] [in a new window]   Table 3. Time Constants () for the Time Course of Inactivation

View larger version (30K): [in this window] [in a new window]   Figure 2. A, Dynamic block of tetrodotoxin-resistant Na+ currents. Upper part: traces of Na+ currents in control, in 100 µM lidocaine, and in 300 µM octanol elicited by the same pulse protocol as in Figure 1A. In the drug, both the 1st and the 10th trace evoked the 2-Hz train, as depicted. Zero current is represented by the horizontal broken line; holding potential was -90 mV. Lower part: dynamic block is revealed by dividing the above traces in the drug (1st and 10th separately) by the trace in the control for each time point. The upper track in each diagram results from the 1st and the lower tracks from the 10th trace. Dotted vertical lines traversing the control peaks illustrate the leftward shift of the peaks in the drug and the amount of dynamic block at the time of the peak current. B, Recovery from inactivation under lidocaine and octanol. Current inactivation was promoted by a conditioning 50-ms stimulus to 10 mV in control and in different lidocaine and octanol concentrations. Recovery was determined by measuring the peak currents evoked by a 5-ms stimulus to 10 mV after variable recovery intervals after the conditioning prepulse. Curves represent nonlinear fits of Equation 4 to the data. Data points are mean values ± SEM from octanol and lidocaine experiments (five each). Lidocaine time constants (with the SE of the fit) (ms) are as follows: 1, fast: 2.9 ± 0.2 (control), 14 ± 2.5 (100 µM), and 32 ± 3.8 (300 µM); and 2, slow: 763 ± 112 (control), 1531 ± 182 (100 µM), and 1763 ± 63 (300 µM). Octanol time constants (with the SE of the fit) (ms) are as follows: 1, fast: 2.3 ± 0.4 (control), 2.1 ± 0.3 (300 µM), and 2.4 ± 0.3 (550 µM); and 2, slow: 625 ± 329 (control), 557 ± 227 (300 µM), and 587 ± 259 (550 µM). a1 is 0.940 ± 0.055, and a2 is 0.249 ± 0.017. With octanol, these values do not change significantly, according to the lack of (measurable) use-dependent block. Lidocaine causes a decrease of a1 (0.1 mM, 0.611 ± 0.031; 0.3 mM, 0.296 ± 0.012) and an increase of a2 (0.1 mM, 0.461 ± 0.017; 0.3 mM, 0.725 ± 0.012), according to the fit of Equation 4 to the data points. This may imply the slow dissociation of lidocaine from its receptor, especially as revealed with increasing lidocaine concentrations.

For competition experiments (Fig. 3), cells (n = 23) were preincubated with octanol in a concentration range from 0.3 to 0.55 mM, causing tonic blockade from 0.16 to 0.79 (1st pulse) and use-dependent blockade from 0.15 to 0.84 (10th pulse). The addition of lidocaine (100–1000 µM) reduced peak currents during the 1st and the 10th pulse (for protocol, see Fig. 1). The lidocaine-induced block in octanol was determined by subtracting the ratio of the peak current of lidocaine in octanol to the peak current in octanol from 1. After a fit to Equation 3 with the Hill coefficient set to 1, each obtained IC₅₀ value was plotted against the octanol block from the corresponding experiment. The horizontal line corresponds to the IC_50,lidocaine according to the inhibition-concentration curve (Fig. 1C), whereas the ascending line was created by Equation 5 and represents the shift of the apparent lidocaine IC₅₀ that is dependent on the octanol block due to competition for one binding site.

View larger version (16K): [in this window] [in a new window]   Figure 3. Simultaneous application of lidocaine and octanol. The 50% inhibitory concentration (IC50) values for the lidocaine block obtained from concentration-inhibition curves after preincubation with octanol are plotted against the fractional block induced by the octanol preincubation. Solid lines show the theoretical change of the apparent lidocaine IC50, assuming competition for either one binding site or two independent binding sites (see text). The dashed lines give a 95% confidence interval for the data points evaluated by linear regression. For clarity, the regression line is not shown.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our main results were that n-octanol and lidocaine inhibit TTX-r Na⁺ currents in single nociceptive rat DRG cells in a reversible and dose-dependent manner but show differences in the modulation of current kinetics and act noncompetitively on TTX-r Na⁺ channels, which implies the involvement of separate binding sites for these substances.

The E_rev of the currents investigated was 27.9 mV, which is close to the calculated equilibrium Na⁺ potential of 32.7 mV for our experimental conditions, thus indicating that we measured Na⁺ currents. TTX-sensitive (TTX-s) Na⁺ currents were inhibited by 100 nM TTX in the bath solution, which blocks 97% of these currents (18). No larger concentrations of TTX were chosen, because the Na_V1.9 (SNS2/NaN) channels become affected by TTX (19), and we wanted our currents to include conductance from the Na_V1.8 and Na_V1.9 channel types, both of which are important in nociception (10).

Our data for activation and availability potentials and the fast recovery from inactivation are consistent with data from other investigators and confirm that the currents measured here relied on TTX-r channels, because kinetic variables for TTX-s channels are different (6,20).

Lidocaine blocks all Na⁺ channel subtypes, including TTX-r channels, in DRG cells (6); for n-octanol, the blockade of Na⁺ currents has been demonstrated in various DRG preparations (9,21). Our data for lidocaine concerning the characteristic concentration-, use-, and voltage-dependent effects on TTX-r current are in accordance with the results from other authors (6).

The putative local anesthetic binding site has been identified in rat brain Na⁺ channels (14). The TTX-r Na⁺ channel in rat DRG cells has the same sequence in the corresponding region (11), and, therefore, a corresponding binding site in TTX-r channels may be assumed. The existence of one binding site for local anesthetic action is supported by our experiments with lidocaine, where the Hill coefficient was close to unity, consistent with a one-to-one binding. The concentration-inhibition curve for octanol is much steeper, giving a Hill coefficient of 1.74. This shows that it does not exert a simple one-to-one stoichiometry and points to an additional or a completely different mode of action in which either allosteric effects or several binding sites might be involved. For TTX-s channels, a Hill coefficient of 2 was found (9), suggesting a similar mode of action.

The larger octanol concentration necessary to block the Na⁺ current results from a very low affinity to binding sites in the Na⁺ channel. It is conceivable that because of the large concentration, the drug binds unspecifically to multiple amino acids in the channel molecule and that there is no specific binding site. If the octanol molecule binds somewhere in the Na⁺ permeation pathway, the channel is blocked. Further, octanol may simply perturb the lipid bilayer and indirectly affect Na⁺ channel function. However, this theory hardly explains dynamic block.

A major difference between lidocaine and octanol is the use dependency of the blockade. Even at very high stimulation frequencies of approximately 10 Hz (Fig. 2C), octanol did not show a use-dependent blockade, which is in accordance with a block of TTX-s Na⁺ currents, in which no use-dependent inhibition for simple n-alkanols has been detected (9,21).

Compared with the logarithm of the octanol/water partition coefficient (logP), lidocaine (logP 2.26) (22) is more water soluble than the hydrophobic, uncharged octanol (logP 3) (23), and according to its negative logarithm of acid ionization constant value of 8.2, it exists preferentially in the charged form at pH 7.4. Hydrophobicity has been described as an important criterion for Na⁺ current block in agents with structural properties similar to those of n-alkanols (9) or local anesthetics (8). The fact that the more lipophilic octanol is less potent than lidocaine may also propose different modes of action. Further, local anesthetics reach their binding site by entering the channel pore from the intracellular site (24), whereas no such mechanism has been reported on alkanols.

Nevertheless, there are alcohols that produce use-dependent blocks in TTX-s Na⁺ currents: the neutral n-octyl-D-glucopyranoside causes a use-dependent block at 1 Hz in rat DRG cells (21). Benzylalcohol produces a frequency-dependent block (10–100 Hz) in Na⁺ channels (25). Differences in structure might be responsible for slower dissociation from the binding site or sites and/or the involvement of sites different from the sites for n-alkanols.

Both lidocaine and octanol interfered with the channels during activation ("time to peak") and inactivation. The mechanisms causing dynamic block, indicated by the exponential decay of fractional current (Fig. 2A, lower part, left part of the dotted vertical line), are not known. Because dynamic block has already begun during channel activation, interference of the drugs with the activation process is most likely. This may be open-channel block, in which drug access to the binding sites is enhanced by the opening of the channel pore and thus increases the association rate of the drugs. Alternatively, it may result from increased affinity at the binding site of the activated channel by decreasing the dissociation rate from the channel. We use the term dynamic block because we cannot distinguish with our experiments between the two different blocking modes.

Despite the observation that octanol produces a dynamic block similar to lidocaine, it shows no use-dependent block. In contrast to lidocaine, octanol quickly dissociates from the binding site during repolarization, as shown in the double-pulse experiments.

Differences between octanol and lidocaine in current kinetics, as well as the different physical-chemical properties, point to different modes of action on the TTX-r current. This was confirmed by competition experiments revealing that the effects were not mediated by the same binding site on the channel. Octanol might act via hydrophobic pathways, with rapid binding and dissociation from its receptor.

Our initial aim was to investigate the effect of ethanol. However, in preliminary experiments, we needed large concentrations to achieve blocking effects, and the cells were destroyed by ethanol concentrations exceeding 30 mM.

We conclude that local anesthetics and alcohols act via different binding sites on the Na⁺ channel molecule and that competition between the drugs does not occur.

	Acknowledgments

 
Supported by departmental funding and institutional research grants of the Charité Medical School.

The authors thank Prof. Dr. Klaus-Dieter Wernecke and Dipl.-Stat. Tania Schink, Department of Statistical Medicine, Humboldt University Berlin, Germany, for performing the nonparametric analysis of variance, and Jordan S. Rettig, PhD, University of Connecticut School of Medicine, University of Connecticut Health Center, University of Connecticut, Farmington, CT, for reviewing the manuscript.

	Footnotes

 
Presented in part at the International Anesthesia Research Society 76th Clinical and Scientific Congress, San Diego, CA, March 16–20, 2002.

	References

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