Abstract
Background and PurposeThe non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV1.7 mutation in vitro.Experimental ApproachHuman wild-type and L858F-mutated NaV1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties.Key ResultsWhile the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents.Conclusion and ImplicationsMexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders.
Highlights
The non-selective sodium channel inhibitor mexiletine hydrochloride [1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride] has been extensively studied and used clinically for decades because of its antiarrhythmic effects (Chew et al, 1979; Woosley et al, 1984; Fenster and Comess, 1986; Monk and Brogden, 1990)
It has been found to be effective in several animal models of chronic pain and it has been suggested as a third-line treatment instead of systemic lidocaine for neuropathic pain syndromes (Jarvis and Coukell, 1998; Kuhnert et al, 1999; Mao and Chen, 2000; Challapalli et al, 2005; Tremont-Lukats et al, 2005; Ebell, 2006; Marmura, 2010)
The L858F mutation in NaV1.7 is one of the best characterized and most common gain-of-function mutations that leads to primary erythromelalgia (PEM) and is associated with a severe phenotype (Han et al, 2007; Samuels et al, 2008; Cheng et al, 2011; Segerdahl et al, 2012)
Summary
The non-selective sodium channel inhibitor mexiletine hydrochloride [1-methyl-2-(2,6-xylyloxy)ethylamine hydrochloride] has been extensively studied and used clinically for decades because of its antiarrhythmic effects (Chew et al, 1979; Woosley et al, 1984; Fenster and Comess, 1986; Monk and Brogden, 1990). Gain-of-function mutations in the related SCN9A gene, which encodes NaV1.7, can result in primary erythromelalgia (PEM), either a familial or a sporadic chronic neuropathic pain syndrome (Dib-Hajj et al, 2005). AND PURPOSE The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties
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