Tachykinin NK1 and NK2 receptor-mediated control of peristaltic propulsion in the guinea-pig small intestine in vitro

The tachykinins substance P and neurokinin A are excitatory cotransmitters of cholinergic enteric neurons, their actions being mediated by NK1, NK2 and NK3 receptors. This study examined which of these receptors are part of the neural circuitry of peristalsis. Peristaltic propulsion in luminally perfused segments of the guinea-pig isolated ileum was elicited by a rise of the intraluminal pressure. The pressure threshold at which peristaltic contractions were triggered was used to quantify drug effects on peristalsis, inhibition of peristalsis being reflected by an increase in the pressure threshold. The NK1, NK2 and NK3 receptor antagonists SR-140333: SR-48968 and SR-142801 (each at 0.1 mu M), respectively, had little effect on peristaltic activity as long as cholinergic transmission was left intact. However, both the NK1 and NK2 receptor antagonist (each at 0.1 mu M) abolished peristalsis after cholinergic transmission via muscarinic receptors had been blocked by atropine (1 mu M) and peristalsis rescued by naloxone (0.5 mu M). When cholinergic transmission via nicotinic receptors was suppressed by hexamethonium (100 mu M) and peristalsis restored by naloxone (0.5 mu M), only the NK2 receptor antagonist (0.I mu M) was able to attenuate peristaltic performance as deduced from a rise of the peristaltic pressure threshold by 106%. The NK3 receptor antagonist (0.1 mu M) lacked a major influence on peristalsis under any experimental condition. It Is concluded that tachykinins acting via NK1 and NK2 receptors sustain intestinal peristalsis when cholinergic neuroneuronal and neuromuscular transmission via muscarinic receptors has been suppressed. NK2 receptors help maintaining peristalsis once cholinergic neuroneuronal transmission via nicotinic receptors has been blocked, whereas NK3 receptors play little role in the neural pathways of peristalsis. (C) 1997 Elsevier Science Ireland Ltd. All rights reserved.