The effect of pregnenolone sulfate (PS) on the capsaicin receptor-mediated current was studied in acutely dissociated rat dorsal root ganglion neurons using the whole-cell voltage-clamp technique. PS acted extracellularly to inhibit the capsaicin-induced current in a not competitive but concentration-dependent manner, with an EC50 of 13 microM and a maximal inhibition of 65%. Furthermore, antagonism of the capsaicin response by PS is neither voltage- nor agonist-dependent, indicating that PS did not act as an open-channel blocker. The inhibitory action of PS on the capsaicin-induced current may provide a basis for reducing capsaicin receptor-mediated nociception.