This study examined the responses of cultured adult human dorsal root ganglion (hDRG) neurons to protons and capsaicin, two substances known to produce pain and hyperalgesia in humans. Both substances were applied to each neuron and responses were examined under both voltage- and current-clamp recording conditions. Sensitivity to protons was tested with rapid acidification of the extracellular fluid from pH 7.35 to 6.0. In neurons nominally clamped near -60 mV, low pH evoked a transient inward current which, in all 40 hDRG neurons tested, was followed by a more sustained inward current. The sustained current was associated with an increase in membrane conductance in 10 neurons, a decrease in 27 neurons, and no overt change in conductance (< 10%) in 3 neurons. Current-clamp recordings in the same neurons showed that the proton-induced sustained net inward current caused a prolonged depolarization of the membrane potential in all 40 hDRG neurons. The prolonged depolarization was associated with action potential discharge in 5 neurons. Unlike low pH, capsaicin evoked a sustained net inward current in only a subset of neurons tested (10 nM: 1/4, 30 nM: 4/8, 100 nM: 11/18, and 10 microM: 10/10 neurons tested). The capsaicin-evoked currents were accompanied by an increase in membrane conductance in 15 neurons, a decrease in 2, and no overt change in conductance in 9 neurons. Capsaicin currents, like proton-induced currents, resulted in prolonged depolarizations (10 nM: 0/4, 30 nM: 5/8, 100 nM: 8/18, and 10 microM: 10/10 neurons tested). The depolarization resulted in the discharge of action potentials in 14 neurons. It is concluded that, while both protons and capsaicin exert excitatory effects on human sensory neurons, multiple membrane mechanisms lead to the depolarization of cultured hDRG neurons by low pH. Inhibition of resting membrane conductances contributes to the responses to low pH in some hDRG neurons.