Calcitonin gene-related peptide facilitates serotonin release from guinea-pig colonic mucosa via myenteric neurons and tachykinin NK2/NK3 receptors.
The ability of calcitonin gene-related peptide (CGRP), to alter the outflow of 5-hydroxytryptamine (5-HT) from the guinea-pig proximal colon, was evaluated using three different isolated preparations: whole colon, mucosa-free muscle layer and submucosa/mucosa preparations. In the presence of the monoamine oxidase A inhibitor, clorgyline, CGRP elicited a concentration-dependent increase in 5-HT outflow from the whole colon, but not from mucosa-free muscle layer preparations. The CGRP-evoked 5-HT outflow was sensitive to tetrodotoxin (TTX) or hexamethonium, but was not detectable in submucosa/mucosa preparations. HCGRP8-37 (3 microM) inhibited the submaximal effect of CGRP on the 5-HT outflow. [Cys(ACM)2,7]hCGRP had a slight stimulant influence on the 5-HT outflow. The selective NK2 and NK3 receptor antagonists, SR48968 or SR142801, respectively, prevented the enhancing effect of CGRP. By contrast, a selective NK1 receptor antagonist L703606, failed to block the effect of CGRP. The enhancing effect of CGRP was mimicked by the NK2 receptor agonist [beta-Ala8]-neurokinin A (NKA)4-10 and the NK3 receptor agonist senktide. The effect of [beta-Ala8]-NKA4-10 on the 5-HT outflow was unaffected by TTX, while the effect of senktide was prevented by TTX, hexamethonium or SR48968. The present data also demonstrated a synergistic action of the NK2 and NK3 receptor agonists on the CGRP-evoked 5-HT outflow. We concluded that CGRP facilitates 5-HT release from the guinea-pig colonic mucosa through an action on myenteric neurons and that this effect is mediated by endogenously released tachykinins, acting via tachykinin NK2/NK3 receptors in cascade. British Journal of Pharmacology (2004) 141, 385-390. doi:10.1038/sj.bjp.0705624
Kojima
Shu-Ichi
S
Department of Pharmacology, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan. s-kojima@dokkyomed.ac.jp
Ueda
Shuichi
S
Ikeda
Masashi
M
Kamikawa
Yuichiro
Y
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009197:Myenteric Plexus / Q000187:drug effects* / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018039:Receptors, Tachykinin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*
D018041:Receptors, Neurokinin-2; D018042:Receptors, Neurokinin-3; D018039:Receptors, Tachykinin; D012701:Serotonin; D015740:Calcitonin Gene-Related Peptide