Inhibition by menthol and its related chemicals of compound action potentials in frog sciatic nerves

Transient receptor potential (TRP) vanilloid-1 (TRPV1) and melastatin-8 (TRPM8) channels play a role in transmitting sensory information in primary-afferent neurons. TRPV1 agonists at high concentrations inhibit action potential conduction in the neurons and thus have a local anesthetic effect. The purpose of the present study was to know whether TRPM8 agonist menthol at high concentrations has a similar action and if so whether there is a structure-activity relationship among menthol-related chemicals.

Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method.

(-)-Menthol and (+)-menthol concentration-dependently reduced CAP peak amplitude with the IC(50) values of 1.1 and 0.93 mM, respectively. This (-)-menthol activity was resistant to non-selective TRP antagonist ruthenium red; TRPM8 agonist icilin did not affect CAPs, indicating no involvements of TRPM8 channels. p-Menthane, (+)-limonene and menthyl chloride at 7-10 mM minimally affected CAPs. On the other hand, (-)-menthone, (+)-menthone, (-)-carvone, (+)-carvone and (-)-carveol (in each of which chemicals OH or O group was added to p-menthane and limonene) and (+)-pulegone inhibited CAPs with extents similar to that of menthol. 1,8-Cineole and 1,4-cineole were less effective while thymol and carvacrol were more effective than menthol in inhibiting CAPs.

Menthol-related chemicals inhibited CAPs and were thus suggested to exhibit local anesthetic effects comparable to those of lidocaine and cocaine as reported previously for frog CAPs. This result may provide information to develop local anesthetics on the basis of the chemical structure of menthol.