title: Melatonin inhibits tachykinin NK₂ receptor-triggered 5-HT release from guinea pig isolated colonic mucosa.
abstract: OBJECTIVE
  Melatonin is involved in the regulation of colonic motility, and sensation, but little is known about the influence of melatonin on 5-hydroxytryptamine (5-HT) release from colonic mucosa. A tachykinin NK₂ receptor-selective agonist, [β-Ala⁸]-neurokinin A(4-10) [βAla-NKA-(4-10)] can induce 5-HT release from guinea pig colonic mucosa via NK₂ receptors on the mucosal layer. The present study was designed to determine the influence of melatonin on 5-HT release from guinea pig colonic mucosa, evoked by the NK₂ receptor agonist, βAla-NKA-(4-10).
  
  
  METHODS
  The effect of melatonin was investigated on the outflow of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) from muscle layer-free mucosal preparations of guinea pig colon, using high-performance liquid chromatography with electrochemical detection.
  
  
  RESULTS
  Melatonin caused a sustained decline in the βAla-NKA-(4-10)-evoked 5-HT outflow from the muscle layer-free mucosal preparations, but failed to affect its metabolite 5-HIAA outflow. The specific MT₃ receptor agonist, 5-methoxycarbonylamino-N-acetyltryptamine mimicked the inhibitory effect of melatonin on βAla-NKA-(4-10)-evoked 5-HT outflow. A MT₃ receptor antagonist prazosin shifted the concentration-response curve of melatonin to the right in a concentration-dependent manner and depressed the maximum effect, but neither a combined MT₁/MT₂ receptor antagonist luzindole, nor a MT₂ receptor antagonist N-pentanoyl-2-benzyltryptamine modified the concentration-response curve to melatonin.
  
  
  CONCLUSIONS
  Melatonin inhibits NK₂ receptor-triggered 5-HT release from guinea pig colonic mucosa by acting at a MT₃ melatonin receptor located directly on the mucosal layer, without affecting 5-HT degradation processes. Possible contributions of MT₁/MT₂ melatonin receptors to the inhibitory effect of melatonin appear to be negligible. Melatonin may act as a modulator of excess 5-HT release from colonic mucosa.
authors.affiliation: Department of Pharmacology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan. s-kojima@dokkyomed.ac.jp
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Kojima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tohei
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikeda
mesh_terms: D000818:Animals; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006168:Guinea Pigs; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D008550:Melatonin / Q000494:pharmacology* / Q000502:physiology; D015288:Neurokinin A / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors*; D012701:Serotonin / Q000378:metabolism*; D014363:Tryptamines / Q000494:pharmacology
chemical_list: C413586:5-methoxycarbonylamino-N-acetyltryptamine; D010446:Peptide Fragments; D044094:Receptors, Melatonin; D018041:Receptors, Neurokinin-2; D014363:Tryptamines; C064218:neurokinin A (4-10), beta-Ala(8)-; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D015288:Neurokinin A; D008550:Melatonin; D011224:Prazosin