title: Menthol pain relief through cumulative inactivation of voltage-gated sodium channels.
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.
authors.affiliation: Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, UMR 6231, CNRS, CS80011, Bd Pierre Dramard, 13344 Marseille Cedex 15, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Gaudioso
authors.forename: Jizhe
authors.initials: J
authors.lastname: Hao
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Martin-Eauclaire
authors.forename: Mélanie
authors.initials: M
authors.lastname: Gabriac
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D006822:Hybrid Cells; D008297:Male; D008610:Menthol / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009433:Neural Inhibition / Q000502:physiology; D009447:Neuroblastoma / Q000378:metabolism / Q000503:physiopathology; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D061251:Primary Cell Culture; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000378:metabolism* / Q000502:physiology
chemical_list: D000700:Analgesics; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C491885:Scn11a protein, mouse; D015222:Sodium Channels; D008610:Menthol