Received for publication September 15, 2005.
Revised December 2, 2005.
Accepted for publication December 2, 2005.

GR-73632 and SPF increase distention-induced peristalsis through activation of NK1 receptors on smooth muscle and ICC

Abstract

Substance P is generally considered an excitatory neurotransmitter as it relates to gut motor activity, although an inhibitory influence of NK1 receptor activation on peristalsis has also been reported. With an optimized in vitro method to assess distention-induced peristalsis, our aim was to clarify the effect of NK1 receptor activation on peristaltic activity and to reveal the mechanisms by which NK1 activation alters peristalsis. Distention of the small intestine of the mouse and guinea pig induced periodic occurrence of rhythmic waves of propagating rings of circular muscle contraction, associated with slow waves and superimposed action potentials, that propelled intestinal contents aborally. Activation of NK1 receptors by GR-73632 and SPF on smooth muscle cells resulted in prolongation of the activity periods and increased action potential generation occurring superimposed on the intestinal slow wave activity. Activation of NK1 receptors on ICC resulted in an increase in slow wave frequency. Slow wave amplitude increased, likely by increased cell to cell coupling. The NK1 antagonist SR 140333 induced a decrease in the slow wave frequency and duration of the activity periods evoked by distention which makes it likely that NK1 receptor activation plays a role in the normal physiological distention-induced generation of peristaltic motor patterns. In summary, NK1 receptors play a role in normal development of peristalsis and NK1 receptor activation markedly increases propulsive peristaltic contractile activity.

Key words: ICC, NK1, enteric nerves, intestinal motility, intestine, prokinetics

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