Shu-ichi Kojima1, Atsushi Tohei, Masashi Ikeda. 1. Department of Pharmacology, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan. s-kojima@dokkyomed.ac.jp
Abstract
BACKGROUND AND PURPOSE: 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). EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: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 pigcolonic 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 pigcolonic mucosa, evoked by the NK₂ receptor agonist, βAla-NKA-(4-10). EXPERIMENTAL APPROACH: 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. KEY 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 AND IMPLICATIONS: Melatonin inhibits NK₂ receptor-triggered 5-HT release from guinea pigcolonic 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: Matthew D Coates; Christine R Mahoney; David R Linden; Joanna E Sampson; Jason Chen; Hagen Blaszyk; Michael D Crowell; Keith A Sharkey; Michael D Gershon; Gary M Mawe; Peter L Moses Journal: Gastroenterology Date: 2004-06 Impact factor: 22.682
Authors: Lucy B Diss; Stephen D Robinson; Yukyee Wu; Sara Fidalgo; Mark S Yeoman; Bhavik Anil Patel Journal: ACS Chem Neurosci Date: 2013-05-01 Impact factor: 4.418