Carbamazepine interacts with a slow inactivation state of NaV1.8-like sodium channels

doi:10.1016/j.neulet.2006.08.070

Neuroscience Letters

Volume 408, Issue 2, 13 November 2006, Pages 129-134

https://doi.org/10.1016/j.neulet.2006.08.070 Get rights and content

Abstract

Carbamazepine was tested on high-threshold TTX-resistant Na⁺ currents (TTX-R-currents), evoked from acutely isolated rat dorsal root ganglion (DRG) cells. Under control conditions, the TTX-R-currents recorded from different DRG cells varied greatly regarding use-dependent inactivation (TTX-R-current UDI), measured as the percent decrease in current amplitude induced by changing the current activation rate from 0.1 Hz to 1.0 Hz. Also, when TTX-R-currents were evoked at 0.1 Hz from a holding potential (hp) of −60 mV, a larger fraction of TTX-R-channels resided tonically in a slow inactivation state in DRG cells with more TTX-R-current UDI versus those with less TTX-R-current UDI. The block of TTX-R-currents evoked from hp −60 mV by 100-μM carbamazepine and the EC50 for carbamazepine block was positively correlated with TTX-R-current UDI. The slope factors estimated for the concentration–response curves averaged 0.68, suggesting the presence of low and high affinity sites. Fitting the data with a two-site binding isotherm gave estimates of 30 μM and 760 μM for the EC50s of the high and low affinity sites, respectively. The fraction of the total fit attributed to the high affinity site was positively correlated with TTX-R-current UDI. Carbamazepine increased the fast and slow time constants for recovery from inactivation and the fraction of the fit attributed to the slow time constant. These data suggest that carbamazepine interacts with a slow inactivation state of TTX-R-channels. This particular mechanism might be exploited in future research aimed at developing pain medications that selectively block Na_V1.8 channels or Na⁺ channels in general.

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Some other AEDs, which are believed to act mainly on fast inactivation have been reported to also influence slow inactivation (Table 6). For example, while carbamazepine does influence slow inactivation of tetrodotoxin (TTX)-sensitive VGSCs (Errington et al., 2008; Sheets et al., 2008), it was reported to decrease the availability of slow inactivated TTX-resistant (Nav1.8-like) VGSCs in dorsal root ganglion neurons (Cardenas et al., 2006; Sheets et al., 2008). Phenytoin has also been reported to modulate the slow inactivation of VGSCs (Quandt, 1988; Niespodziany et al., 2013) but more detailed studies indicated that the drug binds to the fast inactivated state with slow binding and unbinding kinetics rather than to the slow inactivated state (Kuo, 1998; Kuo and Lu, 1997; Kuo and Bean, 1994).
The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation.
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More recently, Song et al. (2009) showed that B1 vitamin treatment reduced neuronal hyperexcitability and lessen alterations of Na+ currents in injured dorsal root ganglia, and proposed that such mechanisms might contribute to its thermal antihyperalgesic effect. Considering that blockade of voltage-dependent Na+ channels in hyperexcitable neurons of the dorsal root or trigeminal ganglia has also been implicated in the analgesic effect of anticonvulsant drugs in neuropathic pain (Cardenas et al., 2006; Caviedes and Herranz, 2002; Priest, 2009), the antihyperalgesic synergism between carbamazepine and B vitamins may be the result of their combined action on this common target. However, the differential effects of the vitamins depending on the type of stimulus used (i.e. cold, heat or mechanical) renders their mechanisms of action even more intriguing and further studies are still necessary to elucidate this issue.
There is mounting evidence that use of B vitamins can help control neuropathic pain. This study investigated if treatment with B1, B6 and B12 vitamins, alone or in combination with carbamazepine, can ameliorate distinct nociceptive behaviors in a model of trigeminal neuropathic pain.
Male Wistar rats were submitted to infraorbital nerve constriction or sham surgery and received a 5-day treatment with one of the B vitamins, a single carbamazepine injection or the association of both treatments and were tested for facial thermal and mechanical hyperalgesia at different time intervals.
Repeated treatment with B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) vitamins (at 180, 180 and 18 mg/kg/day, respectively, for 5 days) prevented the development of heat hyperalgesia after infraorbital nerve injury, but only B12 and B6 treatments attenuated cold and mechanical hyperalgesia, respectively. A single injection of carbamazepine (30 mg/kg) significantly reduced thermal, but not mechanical, hyperalgesia after nerve injury. Combinations of lower doses of each B vitamin (B1 and B6 at 18 mg/kg/day and B12 at 1.8 mg/kg/day for 5 days) with carbamazepine (10 mg/kg) markedly reduced heat hyperalgesia after infraorbital nerve injury. Treatment with B12 (1.8 mg/kg/day) combined with carbamazepine (10 mg/kg) also synergized to attenuate cold hyperalgesia at some time points, but combination of B6 (18 mg/kg/day) with carbamazepine (30 mg/kg) failed to modify mechanical hyperalgesia.
We suggest that B vitamins might constitute a relevant adjuvant to control some aspects of the pain afflicting patients suffering from trigeminal neuropathic pain.
The distribution of low-threshold TTX-resistant Na<sup>+</sup> currents in rat trigeminal ganglion cells
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Probably, the greater than expected decrease in whole-cell Na+ current was the result of the accumulation of slow inactivation of high-threshold TTX-r Na+ channels. Even though typical steady-state inactivation experiments indicate maximum availability for NaV1.8 channels at −60 mV, changing the HP from −80 mV to −60 mV enhances use-dependent slow inactivation of these channels (Cardenas et al., 2006; Tripathi et al., 2006). The observed distribution of low-threshold Na+ currents among TG cells of different diameters was also consistent with the idea that these currents were mediated by NaV1.9 channels.
The distribution of low-threshold tetrodotoxin-resistant (TTX-r) Na⁺ current and its co-expression with high-threshold TTX-r Na⁺ current were studied in randomly selected acutely dissociated rat trigeminal ganglion (non-identified TG cells) and TG cells serving the temporomandibular joint (TMJ-TG cells). Conditions previously shown to enhance Na_V1.9 channel-mediated currents (holding potential (HP) −80 mV, 130-mM fluoride internally) were employed to amplify the low-threshold Na⁺ current. Under these conditions, detectable low-threshold Na⁺ current was exhibited by 16 out of 21 non-identified TG cells (average, 1810 ± 358 pA), and by nine of 14 TMJ-TG cells (average, 959 ± 525 pA). The low-threshold Na⁺ current began to activate around −55 mV and was inactivated by holding TG cells at −60 mV and delivering 40-ms test potentials (TPs) to 0 mV. The inactivation was long lasting, recovering only 8 ± 3% over a 5-min period after the HP was returned to −80 mV. Following low-threshold Na⁺ current inactivation, high-threshold TTX-r Na⁺ current, evoked from HP −60 mV, was observed. High-threshold Na⁺ current amplitude averaged 16,592 ± 3913 pA for TPs to 0 mV, was first detectable at an average TP of −34 ± 1.3 mV, and was ½ activated at −7.1 ± 2.3 mV. In TG cells expressing prominent low-threshold Na⁺ currents, changing the external solution to one containing 0 mM Na⁺ reduced the amount of current required to hold the cells at −80 mV through −50 mV, the peak effect being observed at HP −60 mV. TG cells recorded from with a more physiological pipette solution containing chloride instead of fluoride exhibited small low-threshold Na⁺ currents, which were greatly increased upon superfusion of the TG cells with the adenylyl cyclase (AC) activator forskolin. These data suggest two hypotheses: (1) low- and high-threshold Na_V1.9 and Na_V1.8 channels, respectively, are frequently co-expressed in TG neurons serving the TMJ and other structures, and (2), Na_V1.9 channel-mediated currents are small under physiological conditions, but may be enhanced by inflammatory mediators that increase AC activity, and may mediate an inward leak that depolarizes TG neurons, increasing their excitability.
Lacosamide neurotoxicity associated with concomitant use of sodium channel-blocking antiepileptic drugs: A pharmacodynamic interaction?
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Supporting this hypothesis, in rat dorsal root ganglion cells, blockade of sodium current mediated by carbamazepine was shown to be increased by the proportion of VGSC in the slow inactivated state. It was hypothesized that the drug might bind to a high-affinity site on the slow inactivated VGSC [17]. In the same experiment, carbamazepine was also shown to slow the return of the VGSC from the slow inactivated state to a normal available state, which might enhance the effects of lacosamide.
Lacosamide is a new antiepileptic drug (AED) apparently devoid of major pharmacokinetic interactions. Data from a small postmarketing assessment suggest people who had lacosamide co-prescribed with a voltage-gated sodium channel (VGSC)-blocking AED seemed more likely to discontinue lacosamide because of tolerability problems. Among 39 people with refractory epilepsy who developed neurotoxicity (diplopia, dizziness, drowsiness) on lacosamide treatment given in combination with VGSC-blocking AEDs, we identified 7 (17.9%) without any changes in serum levels of other AEDs in whom the symptoms were ameliorated by dose reduction of the concomitant VGSC-blocking AED. Symptoms in these people seem to have arisen from a pharmacodynamic interaction between lacosamide and other VGSC-blocking AEDs. Slow-inactivated VGSCs targeted by lacosamide might be more sensitive to the effects of conventional VGSC-blocking AEDs. Advising people to reduce concomitantly the conventional VGSC-blocking AEDs during lacosamide uptitration in cases of neurotoxicity might improve the tolerability of combination treatment.
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Comparison of our V1/2 values for inactivation with previous work is not easy because of the wide range of experimental conditions used in previous work, particularly the differing holding potential and pulse protocols used. Among the previous publications on cultured cells or dorsal root ganglion cells, all used fluoride for the internal solution, although for a range of concentrations (Elliott and Elliott, 1993; Akiba et al., 2003; John et al., 2004; Dekker et al., 2005; Cardenas et al., 2006; Choi et al., 2006; Leffler et al., 2007; Zhao et al., 2007). Whether for the rat or human channel, our values for V1/2 are generally more negative than previously-obtained values.
The aim of this work is to characterise the functional properties of human and rat Na_V1.8 channels and to investigate the action of anti-nociceptive agents. Na_V1.8 α-subunits were expressed in mammalian sensory neuron-derived ND7/23 cells, and sodium currents were recorded using whole-cell patch clamp. The current–voltage curves for activation were similar for human and rat Na_V1.8 channels. However, for inactivation, human Na_V1.8 showed more hyperpolarised voltage-dependence than for the rat channel, faster development of inactivation, slower recovery from the fast component of inactivation, and faster recovery from the slow component. Thus, this would imply that the human channel is more inactivated at normal resting potentials. Compounds 227c89, A-803467, V102862, ralfinamide and tetracaine all showed greater affinity for the inactivated state than for the resting state. Compounds A-803467 and V102862 were the most potent, and A-803467 showed greater inactivated state affinity for human than for rat channels. Surprisingly, during recovery from inactivation, an increase in current was observed for V102862 and A-803467, probably due to disinhibition of resting block. Rather than the use-dependent inhibition normally seen with inactivated state blockers, for A-803467 this disinhibition led to an increase in current during repetitive stimulation, while V102862 showed less inhibition than otherwise expected at lower frequencies. Thus the data supports the suggestion that, while both V102862 and A-803467 are potent inhibitors of Na_V1.8, the compound V102862, rather than A-803467, may be useful as an analgesic where physiological firing frequencies are higher.
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Carbamazepine interacts with a slow inactivation state of NaV1.8-like sodium channels

Abstract

Biophys. J.

Neuropharmacology

Neurosci. Lett.

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Pain

Neurosci. Lett.

J. Biol. Chem.

Eur. J. Pharmacol.

A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons

Nature

The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways

Nat. Neurosci.

Use of anticonvulsants for treatment of neuropathic pain

Neurology

Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons

J. Neurosci.

Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na+ currents in rat sensory neurons

Anesthesiology

5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin sensitive rat sensory neurons

J. Neurosci.

Carbamazepine interacts with a slow inactivation state of Na_V1.8-like sodium channels

Role of tetrodotoxin-resistant Na⁺ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons

Effect of drugs used for neuropathic pain management on tetrodotoxin-resistant Na⁺ currents in rat sensory neurons

5HT₄ receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin sensitive rat sensory neurons