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 NK&sub2; receptor-selective agonist, [β-Ala&sup8;]-neurokinin A(4-10) [βAla-NKA-(4-10)] can induce 5-HT release from guinea pig colonic mucosa via NK&sub2; 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 NK&sub2; 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
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 NK&sub2; receptor-selective agonist, [β-Ala&sup8;]-neurokinin A(4-10) [βAla-NKA-(4-10)] can induce 5-HT release from guinea pig colonic mucosa via NK&sub2; 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 NK&sub2; 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 MT&sub3; receptor agonist, 5-methoxycarbonylamino-N-acetyltryptamine mimicked the inhibitory effect of melatonin on βAla-NKA-(4-10)-evoked 5-HT outflow. A MT&sub3; 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 MT&sub1;/MT&sub2; receptor antagonist luzindole, nor a MT&sub2; receptor antagonist N-pentanoyl-2-benzyltryptamine modified the concentration-response curve to melatonin. Conclusions and implications: Melatonin inhibits NK&sub2; receptor-triggered 5-HT release from guinea pig colonic mucosa by acting at a MT&sub3; melatonin receptor located directly on the mucosal layer, without affecting 5-HT degradation processes. Possible contributions of MT&sub1;/MT&sub2; 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.