The response to capsaicin in functional assays suggests multiple sites of capsaicin action. This hypothesis is supported by the results of the present patch-clamp study of isolated dorsal root ganglion cells of the rat. The response to a prolonged application of capsaicin of different concentrations in an external solution with different ion compositions was investigated. Capsaicin evoked up to three distinct current components. The first and second current components could be activated independently. The third component occurred only in the presence of sodium and only in cells in which the second component was also elicited. In an extracellular solution with a physiological composition of ions and 300 nM capsaicin, the peaks of the three components, when evoked, occurred at 10.1 +/- 1.35 s (mean +/- S.E.M., n = 9), 44.0 +/- 2.64 s (n = 16) and 79.0 +/- 8.10 s (n = 5). The activation of the first and/or second current component depended on the concentration of capsaicin. A low concentration predominantly elicited the second component, while a high concentration activated the first and suppressed the second one. The third component seems to be a secondary response of the cell and was not investigated in detail. The activation and decay phases of the first two current components could be fitted by single exponential functions, whereas those of the third component could not. The first and second current components were carried by sodium and calcium. After tachyphylaxis, if the extracellular medium was then acidified to a pH of 6.3, the second component alone could then be elicited by capsaicin. The results demonstrate that capsaicin can elicit different current components that are distinguishable by their time-course, by the effects of acidification of the extracellular solution and by the concentration of capsaicin required to activate these currents. We postulate two distinct binding sites of capsaicin causing two distinct current components. This may account for the variety of physiological responses evoked by capsaicin and the variations in these responses between species.