Abstract

The effects of alcohol monoterpene menthol, a major active ingredient of peppermint plant was tested on the function of human hydroxytryptamine type 3 (5-HT₃) receptors expressed in Xenopus oocytes. 5-HT (1 μM)-evoked currents recorded by two-electrode voltage clamp technique, were reversibly inhibited by menthol in a concentration-dependent (IC₅₀=163 μM) manner. The effects of menthol developed gradually reaching a steady-state level within 10-15 min, and did not involve G-proteins, since GTP-γ-S activity remained unaltered and the effect of menthol was not sensitive to pertussis toxin pretreatment. The actions of menthol were not stereo-selective since (-), (+), and racemic menthol inhibited 5-HT₃ receptor mediated currents to the same extent. Menthol inhibition was not altered by intracellular BAPTA injections and trans-membrane potential changes. The maximum inhibition observed for menthol was not reversed by increasing concentrations of 5-HT. Furthermore, specific binding of 5-HT₃ antagonist [3H]GR65630 was not altered in the presence of menthol (up to 1 mM), indicating that menthol acts as a noncompetitive antagonist of 5-HT₃ receptor. Finally, 5-HT₃ receptor mediated currents in acutely dissociated nodose ganglion neurons were also inhibited by menthol (100 μM). These data demonstrate that menthol, at pharmacologically relevant concentrations, is an allosteric inhibitor of 5-HT₃ receptors.