Menthol is one of the most commonly used chemicals in our daily life, not only because of its fresh flavor and cooling feeling but also because of its medical benefit. Previous studies have suggested that
menthol produces
analgesic action in acute and
neuropathic pain through peripheral mechanisms. However, the central actions and mechanisms of
menthol remain unclear. Here, we report that
menthol has direct effects on the spinal cord.
Menthol decreased both ipsilateral and contralateral
pain hypersensitivity induced by complete
Freund's adjuvant in a dose-dependent manner.
Menthol also reduced both first and second phases of
formalin-induced spontaneous nocifensive behavior. We then identified the potential central mechanisms underlying the
analgesic effect of
menthol. In cultured dorsal horn neurons,
menthol induced inward and outward currents in a dose-dependent manner. The
menthol-activated current was mediated by Cl(-) and blocked by
bicuculline, suggesting that
menthol activates γ-
aminobutyric acid type A receptors. In addition,
menthol blocked
voltage-gated sodium channels and voltage-gated
calcium channels in a voltage-, state-, and use-dependent manner. Furthermore,
menthol reduced repetitive firing and action potential amplitude, decreased neuronal excitability, and blocked spontaneous synaptic transmission of cultured superficial dorsal horn neurons. Liquid chromatography/tandem mass spectrometry analysis of brain
menthol levels indicated that
menthol was rapidly concentrated in the brain when administered systemically. Our results indicate that
menthol produces its central
analgesic action on inflammatory
pain probably via the blockage of voltage-gated Na(+) and Ca(2+) channels. These data provide molecular and cellular mechanisms by which
menthol decreases neuronal excitability, therefore contributing to
menthol-induced central
analgesia.