Desensitization is a process that describes the diminishing effect of a drug upon repeated applications. In regard to capsaicin, the pungent compound in hot pepper, it is well established that removal of extracellular calcium markedly diminishes desensitization. To explore whether this behavior extends to other analogues of capsaicin, we have determined the effect of removing extracellular calcium with capsaicin analogues, zingerone and olvanil, by whole-cell patch clamping cultured rat trigeminal ganglion neurons. Zingerone, like capsaicin, is pungent but has a shorter acyl chain, whereas olvanil is non-pungent and has a longer acyl chain. The currents evoked by 30-s applications of 30 mM zingerone or 1 μM olvanil repeated every 3 min differ in two important ways from the responses evoked by 1 μM capsaicin under these same conditions. In the presence of extracellular calcium, repeated applications of zingerone and olvanil produce nearly complete desensitization. Also in contrast to capsaicin, removing extracellular calcium for these two agonists does not diminish desensitization. These data analyses suggest the existence of calcium-independent pathways that can result in desensitization, and that pungency is not related to the phenomenon of desensitization.