Ionic mechanisms underlying substance P-induced depolarization of the inferior mesenteric ganglion cells of the guinea pig were analyzed by means of microelectrode methods. When the membrane potential was manually clamped at the resting level, substance P caused, in about equal number of neurons, increases and decreases of neuronal input resistance. In the majority of the cells tested the amplitude of substance P-induced depolarization was increased when the membrane was hyperpolarized to the level of EK; it was markedly reduced in a Na+-free media. These results suggest that substance P causes depolarization by simultaneously increasing Na+ and decreasing K+ permeability.