Abstract

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 100 mg/kg reduced both first and second phases of formalin-induced spontaneous nocifensive behavior. Menthol administration also decreased both ipsilateral and contralateral pain hypersensitivity induced by complete Freund's adjuvant. 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 A-type gamma-aminobutyric acid 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. Our results indicate that menthol produces its central analgesic action on inflammatory pain likely via blockage of voltage-gated Na+ and Ca2+ channels. These data provide molecular and cellular mechanisms by which menthol decreases neuronal excitability therefore contributing to menthol-induced central analgesia.