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Pain. 2012 Feb;153(2):473-84. doi: 10.1016/j.pain.2011.11.014. Epub 2011 Dec 14.

Menthol pain relief through cumulative inactivation of voltage-gated sodium channels.

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1
Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, UMR 6231, CNRS, CS80011, Bd Pierre Dramard, 13344 Marseille Cedex 15, France. christelle.gaudioso@univmed.fr

Abstract

Menthol is a natural compound of plant origin known to produce cool sensation via the activation of the TRPM8 channel. It is also frequently part of topical analgesic drugs available in a pharmacy, although its mechanism of action is still unknown. Compelling evidence indicates that voltage-gated Na(+) channels are critical for experiencing pain sensation. We tested the hypothesis that menthol may block voltage-gated Na(+) channels in dorsal root ganglion (DRG) neurons. By use of a patch clamp, we evaluated the effects of menthol application on tetrodotoxin (TTX)-resistant Nav1.8 and Nav1.9 channel subtypes in DRG neurons, and on TTX-sensitive Na(+) channels in immortalized DRG neuron-derived F11 cells. The results indicate that menthol inhibits Na(+) channels in a concentration-, voltage-, and frequency-dependent manner. Menthol promoted fast and slow inactivation states, causing use-dependent depression of Na(+) channel activity. In current clamp recordings, menthol inhibited firing at high-frequency stimulation with minimal effects on normal neuronal activity. We found that low concentrations of menthol cause analgesia in mice, relieving pain produced by a Na(+) channel-targeting toxin. We conclude that menthol is a state-selective blocker of Nav1.8, Nav1.9, and TTX-sensitive Na(+) channels, indicating a role for Na(+) channel blockade in the efficacy of menthol as topical analgesic compound.

PMID:
22172548
DOI:
10.1016/j.pain.2011.11.014
[Indexed for MEDLINE]
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