Tachykinin neurons in the myenteric plexus project on each other implying feed-forward network behaviour. There is also evidence for reciprocal connections between VIP neurons in the submucous plexus. During sustained intestinal distension or during sustained contractions (e.g. phase III of the migrating motor complex), there is a complex, multiphasic mucosal secretory response. This response is abolished in cystic fibrosis, implying electrogenic chloride secretion via the CFTR as the final secretory mechanism. To test the hypothesis that this complex response pattern is due to network behaviour, we have studied the effects of antagonists of different transmission mechanisms in the putative circuitry. We found that blockade of the NK1 receptor (SR 140333 i.v.), blockade of the nicotinic receptor (hexamethonium, hx, i.v.) and serosal administration of lidocaine all delayed the secretory response, but did not consistently affect its final amplitude. Administration of the VIP receptor antagonist [4Cl-D-Phe6,Leu17]-VIP i.v. both delayed the response and reduced its final amplitude. The combination of hx and the VIP antagonist abolished the delayed response. These data are compatible with a simple model consisting of two parallel-coupled networks, a myenteric one operating via NK1 receptors and a submucous one operating via VIP receptors sensitive to [4Cl-D-Phe6,Leu17]-VIP. We also found that the sustained component of the system was significantly upregulated in a mixed population of patients fulfilling the criteria for the irritable bowel syndrome (n = 100). We therefore propose that this syndrome may reflect disturbed network behaviour of myenteric and/or submucous neurons.