Abstract
Substance P is generally considered an excitatory neurotransmitter related to gut motor activity, although an inhibitory influence of neurokinin-1 (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 Ava[l-Pro9,N-MeLeu10] substance P(7-11) (GR 73632) and Sar9, Met(O2)11 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 interstitial cells of Cajal resulted in an increase in slow wave frequency. Slow wave amplitude increased, likely by increased cell-to-cell coupling. The NK1 antagonist (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (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.
Footnotes
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Financial support for this study was from the Canadian Institutes of Health Research. The Koninklijke Maatschappij ter bevordering van de Pharmacie travel grant, the Dr. Saal van Zwanenberg stichting, and the Dr. Hendrik Muller Vaderlandsch Fondsch also supported this research project.
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doi:10.1124/jpet.105.094920.
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ABBREVIATIONS: ICC, interstitial cells of Cajal; ICC-AP, interstitial cells of Cajal associated with Auerbach's plexus (also referred to as ICC-MP or ICC-MY); NK1, neurokinin-1; SR 140333, (S)-1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)piperidin-3-yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride; SPF, Sar9, Met(O2)11; GR 73632, Ava[l-Pro9,N-MeLeu10] substance P(7-11).
- Received September 14, 2005.
- Accepted December 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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