Jpet #203976 Menthol Inhibits 5-ht3 Receptor-mediated Currents

The effects of alcohol monoterpene menthol, a major active ingredient of the 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 concentrationdependent (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 stereoselective 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.