Intracellular methods were used to record electrical behavior of myenteric neurons in guinea-pig ileum in vitro. Calcitonin gene-related peptide (CGRP; 1 nM to 1 microM) and calcitonin (1-100 microM) were applied by addition to the superfusion solution of longitudinal muscle-myenteric plexus preparations. Both peptides were applied also by pressure ejection from fine-tipped micropipettes. CGRP, applied by either method, evoked a long-lasting depolarization of the cell membranes that was dose-dependent (ED50 = 50 nM) and was associated with an increase in the input resistance, suppression of post-spike hyperpolarizing potentials and enhanced excitability in all neurons that were tested. The enhanced excitability was reflected by a significant increase in the number of action potentials evoked by intracellular injection of constant current depolarizing pulses. Enhanced excitability also was apparent as a train of spikes that appeared at the crests of the CGRP-induced depolarization. The excitatory action of CGRP simulated slow synaptic excitation. Application of calcitonin did not evoke any changes in electrical behavior of myenteric neurons. The results are consistent with a neurotransmitter or neuromodulator role for CGRP in the enteric nervous system and suggest that it may participate in local neurohumoral regulation of gastrointestinal effector systems.