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Neurotransmission underlying descending excitatory reflexes evoked by distension was studied in opened segments of guinea-pig ileum and compared with peristalsis in intact segments. The opened segments were distended by inflating a balloon against the serosa at the oral end and changes in muscle length recorded from the anal end. Distension elicited contractions in both circular (CM) and longitudinal (LM) muscle layers. Granisetron, a 5-HT3receptor antagonist (10 nmol L−1to 1 µmol L−1) reduced CM contractions (24% control), without affecting the LM. The P2 receptor antagonist, pyridoxal phosphate-6-azopheyl-2',4'-disulphonic acid (PPADS; 10 µmol L−1), reduced CM contractions to 31% and LM contractions to 39%. Hexamethonium (500 µmol L−1) enhanced LM contractions, but had no effect on CM contractions. Granisetron (1 µmol L−1) had no significant effect on the threshold for peristaltic contractions in a modified Trendelenburg preparation, but decreased the decay time of these contractions by 37%. PPADS (10 µmol L−1) had no significant effect in this preparation. Thus, the descending excitatory pathways to CM and LM can be distinguished pharmacologically; the former depend on 5-HT3and P2 ATP receptors, the latter are independent of 5-HT3receptors. Nicotinic receptors may have little part in either pathway. These properties differ from conventional peristaltic reflexes, which are effectively abolished by nicotinic blockade.