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. 2025 Aug 6;36(12):687-693.
doi: 10.1097/WNR.0000000000002189. Epub 2025 Jun 24.

Menthol preferentially inhibits persistent Na + current mediated by Na V 1.8 in small-sized dural afferent neurons of rats

Michiko Nakamura  1 , Il-Sung Jang  1   2
Affiliations

Menthol preferentially inhibits persistent Na + current mediated by Na V 1.8 in small-sized dural afferent neurons of rats

Michiko Nakamura et al. Neuroreport. .

Abstract

Objective: Menthol is widely used as a cooling agent and an adjunctive analgesic to relieve various painful conditions, such as migraine. As menthol acts as an agonist for the thermosensitive ion channel transient receptor potential melastatin 8 (TRPM8), other ion channels, such as voltage-gated Na + channels, are also involved in the antinociceptive effect of menthol. In this study, we explored the effect of menthol on tetrodotoxin-resistant (TTX-R) Na + channels in nociceptive sensory neurons.

Methods: TTX-R Na + current (I Na ) was recorded from acutely isolated rat dural afferent neurons identified with the fluorescent dye DiI using a whole-cell patch-clamp technique.

Results: Under a voltage-clamp condition, menthol potently decreased the amplitude of the persistent TTX-R Na + current (I Na ) in a concentration-dependent manner, with a minor effect on the transient current. The inhibition of persistent TTX-R I Na by menthol was not affected by the TRPM8 antagonist. Menthol (300 μM) (1) shifted the steady-state fast inactivation relationship to hyperpolarizing ranges without affecting the voltage-activation relationship, (2) accelerated the onset of inactivation, and (3) retarded the recovery from the inactivation of TTX-R Na + channels. Under the current clamp condition, menthol (300 μM) decreased the threshold for action potential generation but reduced the number of action potentials elicited by strong depolarizing current stimuli.

Conclusion: The results of this study suggest that menthol exerts an analgesic effect by preferentially inhibiting persistent TTX-R I Na and modulating the inactivation and recovery kinetics of TTX-R Na + channels.

Keywords: menthol; nociceptive neurons; patch clamp; persistent sodium current.

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