Neuromedin U can exert colon-specific, enteric nerve-mediated prokinetic activity, via a pathway involving NMU1 receptor activation.
OBJECTIVE
The neuromedin U (NMU) receptors, NMU1 and NMU2, are expressed in the gut but their functions are unclear. This study explores the role of NMU in gastrointestinal motility.


METHODS
The effects of NMU were examined in the forestomach and colon isolated from NMU2R wild-type and NMU2R-/- (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.


RESULTS
In the mouse forestomach, NMU (1 nM-10 microM) concentration-dependently induced muscle contraction, in the presence of tetrodotoxin and atropine, in preparations from both wild-type and NMU2R-/- mice (pEC50: 7.9, 7.6, Emax: 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 microM) had no significant effect on baseline muscle tension (n=8), but concentration-dependently potentiated EFS-evoked contractions in preparations from both wild-type and NMU2R-/- mice, pEC50: 8.1, 7.8, Emax: 24%, 21%, respectively, n=6-11. NMU (0.01 nM-0.1 microM, n=5-7) concentration-dependently decreased the interval between waves of peristalsis in the mouse colon (pEC50: 8.8) and increased the rate at which a faecal pellet moved along the guinea-pig colon.


CONCLUSIONS
These results demonstrate that NMU exerts colon-specific, nerve-mediated, prokinetic activity, via a pathway involving activation of NMU1 receptors. This suggests that this receptor may represent a molecular target for the treatment of intestinal motility disorders.
Dass
N B
NB
Gastrointestinal Research, Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline, Harlow, UK.
Bassil
A K
AK
North-Laidler
V J
VJ
Morrow
R
R
Aziz
E
E
Tuladhar
B R
BR
Sanger
G J
GJ
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D003106:Colon / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D017615:Enteric Nervous System / Q000502:physiology*; D005243:Feces; D005769:Gastrointestinal Motility / Q000502:physiology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology*; D010528:Peristalsis / Q000187:drug effects; D017981:Receptors, Neurotransmitter / Q000819:agonists* / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
D008565:Membrane Proteins; D018727:Muscarinic Antagonists; D009479:Neuropeptides; D017981:Receptors, Neurotransmitter; C082444:neuromedin U receptor; C056900:neuromedin U; D013779:Tetrodotoxin; D001285:Atropine