Capsaicin Is a Negative Allosteric Modulator of the 5-HT(3) Receptor

In this study, effects of capsaicin, an active ingredient of the capsicum plant, were investigated on human 5-hydroxytryptamine type 3 (5-HT(3)) receptors. Capsaicin reversibly inhibited serotonin (5-HT)-induced currents recorded by two-electrode voltage clamp method in Xenopus oocytes. The inhibition was time- and concentration-dependent with an IC(50) = 62 μM. The effect of capsaicin was not altered in the presence of capsazepine, and by intracellular BAPTA injections or trans-membrane potential changes. In radio-ligand binding studies, capsaicin did not change the specific binding of the 5-HT(3) antagonist [(3)H]GR65630, indicating that it is a noncompetitive inhibitor of 5-HT(3) receptor. In HEK-293 cells, capsaicin inhibited 5-HT(3) receptor induced aequorin luminescence with an IC(50) of 54 µM and inhibition was not reversed by increasing concentrations of 5-HT. In conclusion, the results indicate that capsaicin acts as a negative allosteric modulator of human 5-HT(3) receptors.