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The actions of substance P (SP), the NK-3 agonist senktide and ATP were studied in single myenteric neurons of guinea pig ileum in vitro. Conventional single electrode voltage clamp was used and responses were compared to those mediated by nicotinic, 5-HT3 and GABAA receptors. Drugs were applied by superfusion or pressure ejection from a fine-tipped pipette. In 8/18 S neurons (RMP= -51 mV, input resistance (IR)= 164 MOhms) pressure applied ATP (1 mM) caused a inward current associated with a increased membrane conductance (gM)(reversal potential (RP) -20 mV). Current latency (< 1s) and decay (< 10s) were similar to nicotinic, 5-HT3 and GABAA responses. Pressure applied SP or senktide (3 mM) caused an inward current in 8/11 AH neurons (RMP= -70 mV, IR= 98 MOhms) of which 2 showed a gM decrease (RP= -98mV), 4 showed a biphasic gM change and 2 showed a gM increase (RP= -9mV). Time course for both responses was .5-1.5 min. (latency: < 1s/gM decrease, > 7s/gM increase). Forskolin (1 mM), caused an inward current which reversed near EK (-98 mV) and selectively occluded the early SP/senktide gM decrease. It is concluded that ATP activates a current similar to that produced by a ligand-gated ion channel, while it is likely that SP/senktide activates a second messenger dependent current.