Menthol preferentially inhibits persistent Na + current mediated by Na V 1.8 in small-sized dural afferent neurons of
Michiko Nakamura1, Il-Sung Jang1,2
1Brain Science & Engineering Institute.
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.
Insights
Menthol relieves pain by inhibiting persistent tetrodotoxin-resistant sodium channels (TTX-R Na+) in sensory neurons. This action modulates channel inactivation and recovery, contributing to menthol's analgesic effects.
Area of Science:
- Neuroscience
- Pharmacology
- Pain Research
Background:
- Menthol is a common analgesic and cooling agent.
- Menthol activates the TRPM8 channel, but its effects on other channels are less understood.
- Voltage-gated sodium channels are crucial in pain signaling.
Purpose of the Study:
- To investigate the effect of menthol on tetrodotoxin-resistant (TTX-R) sodium channels in nociceptive sensory neurons.
- To elucidate the role of TTX-R Na+ channels in menthol's analgesic mechanism.
Main Methods:
- Whole-cell patch-clamp recordings were performed on acutely isolated rat dural afferent neurons.
- Tetrodotoxin-resistant (TTX-R) Na+ current (I Na) was measured.
- The effects of menthol on channel kinetics and action potential generation were analyzed.
Main Results:
- Menthol significantly decreased persistent TTX-R Na+ current amplitude in a concentration-dependent manner.
- Menthol altered the inactivation properties of TTX-R Na+ channels, shifting steady-state inactivation and affecting recovery kinetics.
- Menthol reduced action potential generation in response to strong depolarization.
Conclusions:
- Menthol exerts analgesic effects by preferentially inhibiting persistent TTX-R Na+ channels.
- Modulation of TTX-R Na+ channel inactivation and recovery kinetics by menthol contributes to its pain-relieving properties.
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