Neuroreport · 2025
Menthol preferentially inhibits persistent Na + current mediated by Na V 1.8 in small-sized dural afferent neurons of rats.
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Nakamura Michiko, Jang Il-Sung
Аннотация
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.
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.