Both the neuropeptide calcitonin gene-related peptide (CGRP) and the sensory stimulant drug capsaicin exert excitatory as well as inhibitory actions in the guinea-pig ileum. It has been known that their excitatory effects are due to activation of myenteric neurons. In the present study it has been established that a fairly high concentration (3 microM) of the CGRP antagonist human alpha CGRP (8-37) [hCGRP (8-37)], which has been known to reverse the inhibitory effects of rCGRP, failed to inhibit longitudinal contractions of ileal longitudinal muscle-myenteric plexus strips due to rat (r) CGRP. Instead, a slight enhancement of the contractions was observed, probably due to the inhibition of the relaxant effect. Tachyphylaxis to rCGRP was able to markedly reduce the contractile action of rCGRP but did not influence contractions due to capsaicin (1 microM). It is concluded that myenteric neuronal excitation due to rCGRP involves receptors not sensitive to hCGRP (8-37). Moreover, neuronal excitation by capsaicin does not seem to involve a CGRP-like mediator.