BACKGROUND Calcitonin gene-related peptide (CGRP) is a 37-amino acid peptide localized to primary sensory afferent nerves in the rat stomach. The actions of CGRP in regulating antral neuroendocrine function were examined in vitro through the use of capsaicin, an agent capable of evoking neuropeptide release from peripheral sensory nerve endings. These results were compared with the effects of exogenous CGRP and CGRP antagonist, CGRP8-37. METHODS Rat antral mucosal/submucosal fragments were incubated in either static or dynamic perifusion experiments. Media were assayed for gastrin, somatostatin, CGRP, and acetylcholine. RESULTS Capsaicin, like exogenous CGRP, stimulated antral somatostatin release and inhibited both gastrin release and acetylcholine discharge. Low dose capsaicin (1 x 10(-5) mol/L) caused significant stimulation of CGRP release: 33 +/- 0.2 vs. 14 +/- 1 pg/mL protein; P < 0.001. Tetrodotoxin blocked capsaicin-induced inhibition of acetylcholine release and prevented partially capsaicin-mediated stimulation of CGRP release. The CGRP receptor antagonist CGRP8-37 prevented capsaicin-induced D-cell stimulation and inhibition of G-cell secretion and cholinergic discharge. CONCLUSIONS The effects of capsaicin-induced changes in antral D- and G-cell secretion and acetylcholine discharge are due primarily to release of CGRP. Antral CGRP release from primary sensory afferent nerve terminals may act as a local effector substance to regulate antral neuroendocrine function.