1. Capsaicin, piperine, and zingerone are natural pungent-tasting compounds found in chili pepper, black pepper, and ginger, respectively. These structurally related compounds evoke many of the same physiological responses, but at comparable concentrations capsaicin produces complete tachyphylaxis, piperine produces partial tachyphylaxis, and zingerone can either induce or not induce tachyphylaxis. Whole cell patch-clamp studies were performed on rat trigeminal ganglion cells to determine the similarities and differences between these three pungent compounds. 2. Capsaicin (1 microM) activated a variety of inward currents having peak times ranging from 2 to 46 s that desensitized to various extents ranging from 0 to 100%. The inward currents activated by zingerone (30 mM) had peak times of approximately 2 s and all currents exhibited marked desensitization. The inward currents activated by piperine (100 microM) had peak times of approximately 25 s and all exhibited a small desensitization. 3. Piperine- and zingerone-induced currents were found only in cells that could be activated by capsaicin. 4. Capsazepine (10 microM), an established antagonist of capsaicin-induced currents, inhibited the currents evoked by piperine and zingerone, suggesting that all three compounds activate vanilloid receptors. 5. Dose-response relationships for capsaicin, piperine, and zingerone obtained at a holding potential of -60 mV had threshold and apparent dissociation constants of 0.1 and 0.68 microM, 3 and 35 microM, and 1 and 15 mM, respectively. These values were consistent with those previously obtained in behavioral studies. 6. After seven 30-s applications of 1 microM capsaicin or 100 microM piperine (in a buffer with 2 mM Ca2+), each interspersed with 2-min, 50-s washes, the peak currents were inhibited by approximately 60 and 40%, respectively. In contrast, 30 mM zingerone failed to evoke a current after six applications. After complete tachyphylaxis produced by 30 mM zingerone, 1 microM capsaicin failed to evoke a current, suggesting that these two compounds cross desensitize. 7. The similar physiological responses produced by these three compounds can be rationalized by their binding to receptors and activating currents that can all be inhibited by capsazepine. Their different physiological responses evoked by these compounds can be rationalized, in part, by their very different activation and desensitization kinetics, and perhaps by the existence of different subtypes of vanilloid receptors.