The selective excitant and neurotoxic action of capsaicin on vagal sensory neurons in the rat has been investigated in vitro using three techniques: extracellular recording of compound spike potentials from the whole nerve; intracellular recording from ganglion cells using single-electrode current and voltage clamp; and electron microscopy of the nerve and nodose ganglion. Capsaicin (0.1-10 microM) depolarized vagal sensory C fibres and cell bodies, and produced an increased conductance. The conductance increase appeared to be due to an increased permeability to sodium and calcium, plus a secondary increase in potassium (and perhaps chloride) conductance consequent upon calcium entry. The early entry of calcium seems to be a significant priming event in the neurotoxic process, since dramatic ultrastructural changes take place within a few minutes of capsaicin application, which are minimized by removing extracellular calcium ions. The observations indicate that in sensory C neurons capsaicin opens a conductance of limited specificity and that a resultant large calcium entry is closely involved in the rapid development of cell injury.