Loperamide inhibits tachykinin NK3-receptor-triggered serotonin release without affecting NK2-receptor-triggered serotonin release from guinea pig colonic mucosa.
The effect of loperamide on tachykinin NK(2)- and NK(3)-receptor-mediated 5-HT outflow from guinea pig colonic mucosa was investigated in vitro. The selective tachykinin NK(2)-receptor agonist [beta-Ala(8)]-neurokinin A(4-10) (betaAla-NKA) or the selective NK(3)-receptor agonist senktide elicited an increase in 5-HT outflow from whole colonic strips, but not from mucosa-free muscle layer preparations. The enhancing effect of betaAla-NKA and senktide was prevented by the selective NK(2)-receptor antagonist GR94800 or the selective NK(3)-receptor antagonist SB222200. Loperamide concentration-dependently suppressed the senktide-evoked 5-HT outflow, but failed to affect the betaAla-NKA-evoked 5-HT outflow. The kappa-opioid receptor antagonist nor-binaltorphimine or the delta-opioid receptor antagonist naltrindole displaced the concentration-response curve for the suppressant action of loperamide to the right without significant depression of the maximum. However, the mu-opioid receptor antagonist CTOP did not affect the suppressant effect of loperamide. We concluded that the NK(3) receptor-triggered 5-HT release from colonic mucosa is suppressed by loperamide-sensitive mechanisms, whereas the NK(2)-receptor-triggered 5-HT release is loperamide-insensitive. Our data also suggest that the suppressant effect of loperamide is probably mediated by the activation of kappa- and delta-opioid receptors located on intrinsic neurons.
Kojima
Shu-Ichi
S
Department of Pharmacology, Dokkyo University School of Medicine, Tochigi, Japan. s-kojima@dokkymed.ac.jp
Ikeda
Masashi
M
Kamikawa
Yuichiro
Y
D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D006168:Guinea Pigs; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008139:Loperamide / Q000494:pharmacology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D018039:Receptors, Tachykinin / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000145:classification / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
D000930:Antidiarrheals; D010446:Peptide Fragments; D018039:Receptors, Tachykinin; C054724:senktide; D012701:Serotonin; D013373:Substance P; D008139:Loperamide