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PAIN MEDICINE

The Effects of Class Ic Antiarrhythmics on Tetrodotoxin-Resistant Na⁺ Currents in Rat Sensory Neurons

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Japan

Address correspondence and reprint requests to Shuji Dohi, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu-City, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp

	Abstract

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IV or oral administration of antiarrhythmics has been reported to be effective for relieving neuropathic pain. Recent reports have indicated that tetrodotoxin-resistant (TTX-R) Na⁺ channels play important roles in the nerve conduction of nociceptive sensation. In the present study, we investigated the effects of flecainide, pilsicainide (class Ic antiarrhythmics), and lidocaine (a class Ib drug) on TTX-R Na⁺ currents in rat dorsal root ganglion neurons using the whole-cell patch-clamp method. Flecainide, pilsicainide, and lidocaine reversibly blocked the peak amplitude of TTX-R Na⁺ currents in a concentration-dependent manner with half-maximum inhibitory concentration values of 8.5 ± 6.6 µM (n = 7), 78 ± 6.9 µM (n = 7), and 73 ± 6.8 µM (n = 7), respectively. Each drug shifted the inactivation curve for the TTX-R Na⁺ currents in the hyperpolarizing direction and caused a use-dependent block. We also studied an interaction between these antiarrhythmics on TTX-R Na⁺ channels. Additional application of flecainide or pilsicainide to lidocaine resulted in an additive increase of tonic and use-dependent block. These results suggest that the inhibition of TTX-R Na⁺ currents of dorsal root ganglion neurons by such antiarrhythmics is attributable, at least partly, to their antinociceptive effects.

IMPLICATIONS: We examined the effect of class Ic antiarrhythmics on tetrodotoxin-resistant Na⁺ channels that are important in nociception. They blocked these channels in a concentration- and use-dependent manner, with a minor difference from those of lidocaine, a Ib antiarrhythmic.

	Introduction

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Neuropathic pain after a peripheral nerve injury is difficult to treat and is often resistant to conventional analgesics. Spontaneous or evoked hyperexcitability of the peripheral nerve after injury is considered to be a principal feature of the underlying pathophysiology associated with neuropathic pain syndrome (1). Because the Na⁺ channels of sensory neurons play an important role in controlling their membrane excitability, it is not surprising that Na⁺ channel blockers are chosen for the treatment of neuropathic pain. Indeed, Na⁺ channel blockers, such as local anesthetics, anticonvulsants, or antiarrhythmics, have been used clinically for the treatment of neuropathic pain, and in some cases, these drugs have beneficial effects when added to conventional analgesics (2). Lidocaine and mexiletine, which are class Ib antiarrhythmic drugs according to the Vaughan Williams classification, are effective for neuropathic pain (3). Flecainide is a class Ic antiarrhythmic drug whose action in blocking the Na⁺ channel is potent and long lasting compared with class Ib drugs (4). Previous clinical studies have demonstrated the effectiveness of the class Ic antiarrhythmic drug flecainide on neuropathic pain (5,6). Moreover, flecainide’s analgesic effect also has been reported in the rat chronic constrictive injury (CCI) model (7). Pilsicainide is also a class Ic drug (8). There have been no studies examining the potential analgesic effect of pilsicainide.

Several reports have indicated that tetrodotoxin-resistant (TTX-R) Na⁺ channels play important roles in the generation of nociceptive impulses in peripheral nerve fibers under both physiologic (9) and pathophysiologic conditions (10). Nerve terminals in distal limb neuromas and skin from patients with chronic local hyperalgesia and allodynia showed marked increases of TTX-R Na⁺ channel-immunoreactive fibers, suggesting that this channel may be related to the hypersensitive state (11). In addition, inhibition of neuropathic pain by knock-down of the TTX-R Na⁺ channel protein by means of specific antisense oligodeoxynucleotides suggests that this channel’s activity links to neuropathic pain and may be an effective target for the treatment of such a condition (12). The blocking effects of class Ib antiarrhythmics and other Na⁺ channel blockers, such as carbamazepine and amitriptyline, have been reported on TTX-R Na⁺ channels in rat dorsal root ganglion (DRG) neurons (13). However, there have been no studies investigating the potential analgesic effect of class Ic drugs at the DRG level. We thus attempted to compare the effects of Ic antiarrhythmics, flecainide and pilsicainide, and a Ib drug, lidocaine, on the TTX-R Na⁺ currents of rat DRG neurons. We also investigated the combined effects of flecainide plus lidocaine and pilsicainide plus lidocaine on the TTX-R Na⁺ currents.

	Methods

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Adult Sprague-Dawley rats (200–250 g) were anesthetized using an intraperitoneal injection of pentobarbital (200 mg/kg) and then were killed by decapitation. The procedures used in the present study conformed to the Guideline Principles in the Care and Use of Animals approved by the Council of the American Physiologic Society, and the experimental protocols were approved by our Institutional Committee for Animal Care. DRGs were removed along the cervical, thoracic, and lumbar sections of the spinal cord. The DRGs were incubated at 37°C for 35–40 min in Tyrode solution (for composition, see below) containing 2 mg/mL of collagenase (Type 1; Sigma, St Louis, MO) and 5 mg/mL of dispase II (Boehringer Mannheim, Indianapolis, IN). After being washed three times with fresh, enzyme-free Tyrode solution, single neuronal cells were obtained by gentle agitation in Tyrode solution through a small-bore Pasteur pipette. The cells were placed on glass coverslips and incubated in a humidified atmosphere of 5% CO₂ at 37°C for 2–8 h before being used.

A coverslip carrying the cells was placed in a small organ bath on the stage of an inverted microscope (Olympas IX70, Tokyo, Japan). Na⁺ currents were recorded using the whole-cell patch clamp technique (14). Experiments were conducted at 22°C–24°C. Patch pipettes were made from glass capillaries using a six-step puller (P-97; Sutter Instrument Company, Novato, CA), and their tips were fire-polished using a microforge (MF-830; Narishige, Tokyo, Japan) to give a final resistance of 1.0–2.0 M. Current recordings were performed with an Axopatch 200B patch-clamp amplifier (Axon Instruments, Union City, CA) in the voltage-clamp mode, and signals were digitized by a 12-bit AD-converter (digidata 1200B, Axon Instruments) filtered at 5 kHz, sampled at 20 kHz using PClamp 8.0 software (Axon Instruments), and stored on the hard disk of a personal computer, which also served as the stimulus generator. Series resistance was compensated >80%. A P/4 protocol (15) was used for leak subtraction. Origin v.6 software (Microcal Software, Inc, North Hampton, MA) was used for preparation of figures and for fitting procedures.

The Tyrode solution was composed of (mM) NaCl 140.0, KCl 4.0, MgCl₂ 2.0, glucose 10.0, HEPES 10.0, and adjusted to a pH value of 7.4 with NaOH. The pipette solution was as follows (mM): CsF 135.0, NaCl 10.0, HEPES 5.0, and EGTA 3.0 (adjusted to a pH value of 7.0 with CsOH). The external solution was as follows (mM): NaCl 25.0, tetramethylammonium chloride 75.0, tetraethylammonium chloride 20.0, CsCl 5.0, CaCl₂ 1.8, MgCl₂ 1.0, glucose 25.0, and HEPES 5.0 (adjusted to a pH value of 7.4 with tetraethylammonium-OH). TTX 200 nM was added to suppress TTX-sensitive (TTX-S) Na⁺ currents.

The drugs used were flecainide chloride (Eizai, Tokyo, Japan), pilsicainide chloride (Suntory, Tokyo, Japan), and lidocaine (Sigma). The recording chamber (0.8 mL) was perfused with 8 mL of the external solution containing various concentrations of drugs freshly prepared before the current measurements.

All values in the text are expressed as mean ± SD. Statistical significance was assessed by using a Student’s paired or unpaired t-test; differences were considered significant when P < 0.05.

	Results

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TTX-R Na⁺ currents were recorded from DRG cells having a diameter of <30 µm (25 ± 4.8 µm; n = 132), which expressed both TTX-S and TTX-R Na⁺ currents in variable proportions. In these cells, TTX-S Na⁺ currents were blocked by adding TTX into the external solution, and the remaining TTX-R Na⁺ currents were used for this study.

Na⁺ currents were elicited by depolarizing steps to –10 mV from a holding potential of –70 mV. The impulse protocol was applied 20 min after the completion of whole-cell patch in external control solution, 5 min after perfusion with different drug concentrations, and again in external control solution to check reversibility.

Flecainide, pilsicainide, and lidocaine reversibly inhibited TTX-R Na⁺ currents. Flecainide at 10 µM blocked the peak currents by 55% ± 8% (n = 7). Pilsicainide and lidocaine at 100 µM blocked by 55% ± 8% and 57% ± 8% (n = 7), respectively (Fig. 1A). Current inhibition by the drugs was dose-dependent and complete at large concentrations (Fig. 1B). The fractional block (f_b) was plotted against drug concentration (c). The lines were obtained by curve fitting of the following Hill equation to the data points: f_b = 1/(1 + [IC₅₀/c] ^h), where h is the Hill coefficient. The half-maximal inhibitory concentration (IC₅₀) values of flecainide, pilsicainide, and lidocaine were 8.5 ± 6.6 µM, 78 ± 6.9 µM, and 73 ± 6.8 µM, respectively. Hill (h) coefficient values were 1.08 ± 0.09, 1.08 ± 0.11, and 1.07 ± 0.10, respectively.

View larger version (14K): [in this window] [in a new window]   Figure 1. (A) Effects of antiarrhythmics on tetrodotoxin-resistant (TTX-R) Na+ currents in rat dorsal root ganglion (DRG) cells. In each set of currents, dashed lines represent the current traces elicited in the control solution; solid lines are traces obtained in the presence of each drug. The inset shows the protocol of a single-pulse sequence using a 50-ms test pulse. Holding potential was –70 mV. (B) Concentration-response curves for the blocking action of each antiarrhythmic drug (square, flecainide; triangle, pilsicainide; circle, lidocaine). Fractional block of the peak currents elicited by stepping (for 50 ms) from –70 mV to –10 mV is plotted against drug concentration. Data points are mean values, and error bars represent SD. Curves were drawn according to the Hill equation (see text); (n = 7 for each point).

View larger version (34K): [in this window] [in a new window]   Figure 2. Current-voltage relationships for tetrodotoxin-resistant (TTX-R) Na+ currents. TTX-R Na+ currents were evoked by stepping (50-ms duration; one step every 10 s) to potentials of –55 to +40 mV in 5-mV increments from a holding potential of –70 mV. Current tracings of TTX-R Na+ currents before (a) and after (b) application of (A) 3 µM of flecainide, (B) 30 µM of pilsicainide, and (C) 30 µM of lidocaine. (c) Current-voltage relationship for peak amplitudes of TTX-R Na+ currents before and after application of each drug and after removal of each drug.

View larger version (14K): [in this window] [in a new window]   Figure 3. Effects of antiarrhythmics on the voltage-dependent inactivation of tetrodotoxin-resistant (TTX-R) Na+ channels. Conditioning pulses stepped (for 150 ms) from –100 mV to –10 mV in 10-mV increments were followed by a 5-ms test pulse stepped to –10 mV from the various prepulse potentials. The current amplitude (I) is normalized to the maximum control current amplitude (Imax) and plotted against the membrane potential attained by use of the conditioning pulse in the absence or presence of each drug. Curves were drawn according to the Boltzmann equation (see text). Each point represents mean value, and error bars are SD. (n = 6; each concentration of drug) Open square, control; closed square, 10 µM of flecainide; open triangle, control; closed triangle, 100 µM of pilsicainide; open circle, control; and closed circle, 100 µM of lidocaine.

Each drug caused a use-dependent block of the TTX-R Na⁺ current during repetitive stimulation. TTX-R Na⁺ currents were elicited repeatedly by applying successive depolarizing pulses at 0.2, 5, or 20 Hz in the absence and presence of 3 µM of flecainide, 30 µM of pilsicainide, or 30 µM of lidocaine. These drug concentrations are approximately 25% inhibition doses as judged from the dose-response curve (Fig. 1B) of each drug. Currents were evoked by stepping (for 10 ms) to –10 mV from a holding potential of –70 mV at 1 of 3 different frequencies. The ratio I₁₅/I₁ (current amplitude at 15th pulse/current amplitude at 1st pulse) at each frequency is listed in Table 1. Although the current amplitude under control conditions progressively decreased with increasing pulse number because of the accumulation of channel inactivation, the decrements were significantly enhanced in the presence of flecainide and pilsicainide at 0.2, 5, and 20 Hz or lidocaine at 5 and 20 Hz.

View larger version (28K): [in this window] [in a new window]   Figure 4. (A) Tonic block of the peak tetrodotoxin-resistant (TTX-R) Na+ currents by the three drugs. Columns are mean, and error bars are SD. Data in the left-hand group of columns were obtained after a single treatment with either 3 µM of flecainide (Fl), 30 µM of pilsicainide (Pil), or 30 µM of lidocaine (Lid). Those in the right-hand columns were obtained after additional application of 3 µM of Fl or 30 µM of Pil to 30 µM of Lid (n = 6; each column). *P < 0.05 versus a single application of lidocaine. P < 0.05 versus a single application of flecainide. P < 0.05 versus a single application of pilsicainide. (B) Use-dependent block of the peak TTX-R Na+ currents at a frequency of 5 Hz. Normalized TTX-R Na+ peak currents in the control and in the presence of 3 µM of flecainide (Fl), 30 µM of lidocaine (Lid), and a mixture of 3 µM of Fl plus 30 µM of Lid were plotted against pulse number. Each point represents mean value, and error bars are SD (n = 6; each point). *P < 0.05 versus control 15th current value. P < 0.05 versus a single application of flecainide. P < 0.05 versus a single application of lidocaine. (C) Normalized TTX-R Na+ peak currents. Normalized TTX-R Na+ peak currents in control and in the presence of 30 µM of pilsicainide (Pil), 30 µM of lidocaine (Lid), and a mixture of 3 µM of Pil plus 30 µM of Lid. Each point represents mean value, and error bars are SD (n = 6; each point). *P < 0.05 versus control 15th current value. P < 0.05 versus a single application of flecainide. P < 0.05 versus a single application of lidocaine.

	Discussion

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The present results indicated that both flecainide and pilsicainide, as well as lidocaine, blocked TTX-R Na⁺ channels in a dose- and use-dependent manner. These drugs shifted the voltage-dependent inactivation curve in the hyperpolarizing direction. Combined application of flecainide or pilsicainide with lidocaine increased tonic and use-dependent block additively compared with those obtained using a single drug.

In the present study, we found that Ic antiarrhythmics, flecainide and pilsicainide, reduced TTX-R Na⁺ currents in rat DRG neurons in a dose-dependent manner similar to the effect of the Ib antiarrhythmic lidocaine. At a holding potential of –70 mV, which is near the resting membrane potential, flecainide was the most potent of these three drugs as judged from the IC₅₀ values. Our IC₅₀ value of 73 µM for lidocaine is somewhat smaller than that of 128 µM reported by Bräu et al. (13). This difference may be explained by the different experimental settings used, such as culture media, culture duration, composition of external solution, or the method used to elicit Na⁺ currents. The plasma concentration of flecainide, pilsicainide, and lidocaine required to produce an antiarrhythmic action is 0.2–1 µg/mL (0.4–2 µM), 0.2–0.9 µg/mL (0.6–3 µM), and 1.5–5 µg/mL (4.5–15 µM), respectively, in humans (16). These plasma levels are similar to those we have used clinically to treat patients with chronic pain (3,6). The plasma level of flecainide required to suppress pain and spontaneous discharge in the rat neuropathic pain model is 1.5 to 3 µg/mL (3–6 µM) (7), and the minimal plasma level of lidocaine for pain suppression in patients suffering from peripheral nerve injury pain is 1.5 µg/mL (6 µM) (17). Because the present results revealed that the IC₅₀ value of flecainide was close to the therapeutic plasma levels, and flecainide (as well as pilsicainide and lidocaine) also produced use-dependent block, flecainide may have enough potential to reduce currents through TTX-R Na⁺ channels in the DRG neurons and thus alleviate pain. However, the IC₅₀ value of pilsicainide is much larger than the therapeutic doses for clinical applications. Pilsicainide would be less effective in systemic administration to suppress nociceptive transmission, as judged from IC₅₀.

Lidocaine has been reported to be more potent at blocking TTX-S Na⁺ currents than TTX-R Na⁺ currents in rat DRG neurons (18), which is consistent with our result in the present study. There have been no studies on effects of flecainide and pilsicainide on the TTX-S Na⁺ channels. In the present study, flecainide and pilsicainide had similar blocking potencies on the TTX-S Na⁺ channels using 10 µM of flecainide and 100 µM of pilsicainide.

The Na⁺ current blockade of flecainide and pilsicainide seemed to be voltage-dependent, as evidenced by the shift of the steady-state TTX-R Na⁺ channel inactivation curve to a more negative direction. This could agree with results obtained with Na⁺ channels of cardiac myocytes (19,20). Lidocaine also shifted the inactivation curve for the TTX-R Na⁺ channel in the hyperpolarizing direction; this is consistent with a previous study (21). Because the hyperpolarizing shift of the inactivation curve indicates that the fraction of inactivated Na⁺ channels increases at the resting membrane potential after application of these drugs, it is suggested that these drugs would reduce the membrane excitability of DRG neurons. A use-dependent block of TTX-R Na⁺ channels has been demonstrated for several drugs such as local anesthetics, antiarrhythmics, and anticonvulsants in various preparations (13,21), and increased frequency of depolarizing pulses is attributed to their binding to open and inactivated channel states (22). In this regard, perhaps flecainide and pilsicainide could produce a use-dependent block by means of a similar mechanism and thus contribute to reducing the impulse in an ectopic site of an injured nerve.

Different from lidocaine, flecainide can be administered orally and IV for analgesic effect. A few clinical studies have described that flecainide has an analgesic effect. Dunlop et al. (5) reported that oral flecainide was effective in reducing cancer-related neuropathic pain. Ichimata et al. (6) also showed that IV and oral administration of flecainide (2 mg/kg) to patients with postherpetic neuralgia significantly reduced the degree of pain. The results of the present electrophysiological study may support the clinical efficacy of flecainide for neuropathic pain. Although there have been no studies on the analgesic effect of pilsicainide, the present study suggests that it may also have an analgesic effect. Further clinical investigation is required to clarify this hypothesis.

According to the modulated receptor hypothesis (23), Na⁺ channels have a common receptor site for antiarrhythmics. Thus, an admixture of large concentrations of two such drugs would induce competitive displacement of one drug by another. Flecainide and pilsicainide are supposed to block the Na⁺ channel mainly during the activated state, whereas lidocaine blocks during the inactivated state (16). Because the activated state precedes the inactivated one in every depolarizing cycle and the binding and unbinding of lidocaine is much faster than those of flecainide or pilsicainide, the competition between lidocaine and the other two drugs would be inconspicuous. There is a possibility of the development of drug interaction between Ic and Ib drugs when they are administered either concurrently or with an interval between administering in cases of treatment for cardiac arrhythmia as well as pain. Although we could not find any data indicating a potential interaction between flecainide and lidocaine or pilsicainide and lidocaine on cardiac muscle cells, the results observed in a use-dependent block of DRG neurons may suggest that a combination of flecainide and lidocaine or pilsicainide and lidocaine would provide a greater analgesic effect for patients with neuropathic pain.

However, two TTX-R Na⁺ channels, Na_v1.8 and Na_v1.9, are preferentially expressed in small DRG neurons and are thought to play specialized roles in pain sensation. Previous studies indicate that the two TTX-R Na⁺ channels differ in their electrophysiological properties (24). In the present study, we focused only on the whole-cell TTX-R Na⁺ currents. Although it is beyond the scope of the present study to comment on the potential effects of the drugs used on the different types of TTX-R channels, both of the described sensory neuron-specific TTX-R channels, Na_v1.8 and Na_v1.9, play a critical role in neuronal excitability (10,25).

Because TTX-R Na⁺ currents recorded in DRG cells from a rat model of CCI, a model of neuropathic pain, have been reported to show electrophysiological properties different from those of healthy rats (26), the results in DRG neurons obtained from healthy rats may have some limitations regarding their roles in neuropathic pain. CCI shifted the voltage dependence of activation and inactivation of the TTX-R Na⁺ currents to a more negative direction. Under these models with neuropathic pain, the cells may be more sensitive to the use-dependent blockers because voltage dependence of drug affinity may also be shifted to a more negative direction. All drugs used in the present study may be useful to block the TTX-R Na⁺ currents under neuropathic pain conditions because they showed a use-dependent block effect on the TTX-R Na⁺ channels. However, there have been no studies to compare the responses to the TTX-R Na⁺ channel blockers between the intact cells and the cells from animals of neuropathic models. Further studies using the cells from neuropathic pain models are required to elucidate this issue.

In conclusion, flecainide and pilsicainide block TTX-R Na⁺ channels of rat DRG neurons in a dose- and use-dependent manner. These drugs shifted the voltage-dependent inactivation curve in the hyperpolarizing direction. The results of the present study suggest that class Ic antiarrhythmics have an effect similar to that of class Ib lidocaine. The inhibition of class Ic drugs of TTX-R Na⁺ currents may contribute to their antinociceptive effects.

	Acknowledgments

 
Supported, in part, by Grant-in-Aid for Scientific Research No. 14207059 (Ministry of Education, Science and Culture, Tokyo, Japan).

	Footnotes

 
Presented, in part, at the annual meeting of the American Society of Anesthesiologists, Orlando, FL, October 12–16, 2002.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Osawa, Y. Articles by Dohi, S. Search for Related Content PubMed PubMed Citation Articles by Osawa, Y. Articles by Dohi, S. Related Collections Mechanisms Pain Pharmacology