Neurohumoral control of goblet cell degranulation in isolated segments of the guinea pig main pancreatic duct was examined using morphometric procedures. Goblet cells represent 25-30% of the epithelial cell population at the head of the main pancreatic duct, a percentage that decreases to 5-10% as the distance from the ampulla increases. Carbachol, bombesin, and vasoactive intestinal peptide (VIP) each stimulated degranulation of duct goblet cells, although cholecystokinin octapeptide, secretin, and histamine did not. The stimulatory effects of carbachol on goblet cell degranulation in isolated pancreatic ducts were blocked by atropine and enhanced by simultaneous exposure to VIP. These observations indicate that goblet cells in guinea pig pancreatic ducts express bombesin, VIP, and muscarinic cholinergic receptors and that multiple intracellular signaling pathways are involved in the regulation of goblet cell degranulation.