Neuromedin U can exert colon-specific, enteric nerve-mediated prokinetic activity, via a pathway involving NMU 1 receptor activation

Abstract

Background and purpose: The neuromedin U (NMU) receptors, NMU 1 and NMU 2, are expressed in the gut but their functions are unclear. This study explores the role of NMU in gastrointestinal motility. Experimental approach: The effects of NMU were examined in the forestomach and colon isolated from NMU 2R wild-type and NMU 2R-/- (knockout) mice, looking for changes in muscle tension and in nerve-mediated responses evoked by electrical field stimulation (EFS), and in models of peristalsis in mouse colon and faecal pellet transit in guinea-pig colon. Key results: In the mouse forestomach, NMU (1 nM-10 μM) concentration-dependently induced muscle contraction, in the presence of tetrodotoxin and atropine, in preparations from both wild-type and NMU 2R-/- mice (pEC 50: 7.9, 7.6, E max: 0.26, 0.20g tension, respectively, n=8 each concentration). The same concentrations of NMU had no consistent effects on the responses to EFS (n=8). In the mouse colon, NMU (0.1 nM-1 μM) had no significant effect on baseline muscle tension (n=8), but concentration-dependently potentiated EFS-evoked contractions in preparations from both wild-type and NMU 2R-/- mice, pEC 50: 8.1, 7.8, E max: 24%, 21%, respectively, n=6-11. NMU (0.01 nM-0.1 μM, n=5-7) concentration-dependently decreased the interval between waves of peristalsis in the mouse colon (pEC 50: 8.8) and increased the rate at which a faecal pellet moved along the guinea-pig colon. Conclusions and implications: These results demonstrate that NMU exerts colon-specific, nerve-mediated, prokinetic activity, via a pathway involving activation of NMU 1 receptors. This suggests that this receptor may represent a molecular target for the treatment of intestinal motility disorders. © 2007 Nature Publishing Group All rights reserved.