Dual effect of trimebutine on contractility of the guinea pig ileum via the opioid receptors.
Preparations of longitudinal muscle attached to myenteric plexus from guinea pig ileum were used to observe the effect of trimebutine on intestinal motility. Electrical stimulation at 0.2 Hz and 5 Hz produced contraction mediated by the release of acetylcholine in the preparations. The response to low-frequency stimulation (0.2 Hz) was inhibited by trimebutine (10(-8)-10(-5) mol/L), and the response to high-frequency stimulation (5 Hz) was enhanced by the drug at low concentrations (10(-8)-10(-7) mol/L) and inhibited by high concentrations (10(-6)-10(-5) mol/L). This enhancement was mimicked by [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, and was antagonized by naloxone but not by MR2266. Enhancement by trimebutine was inhibited by yohimbine. Trimebutine (greater than or equal to 10(-8) mol/L) inhibited stimulation (5 Hz)-evoked release of norepinephrine, and the trimebutine effect was antagonized by naloxone but not by MR2266. Low concentrations of trimebutine inhibit norepinephrine release via the mu-opioid receptor and enhance intestinal motility by preventing the adrenergic inhibition of acetylcholine release. Inhibition by trimebutine was antagonized either by naloxone or MR2266. High concentrations of trimebutine may inhibit acetylcholine release via the mu- and kappa-opioid receptors, after which the intestinal motility is inhibited. Trimebutine at further high concentrations (greater than 10(-5) mol/L) contracted single smooth muscle cells from the circular muscle layers but not from the longitudinal muscle layers. The usual dose of trimebutine may exert dual effect on the intestinal motility indirectly through cholinergic and adrenergic neurons without direct effect on the smooth muscle.
Taniyama
K
K
Department of Pharmacology, Kobe University School of Medicine, Japan.
Sano
I
I
Nakayama
S
S
Matsuyama
S
S
Takeda
K
K
Yoshihara
C
C
Tanaka
C
C
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists; D009638:Norepinephrine / Q000378:metabolism; D011957:Receptors, Opioid / Q000187:drug effects; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D014287:Trimebutine / Q000494:pharmacology*
D004745:Enkephalins; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009270:Naloxone; D020881:Enkephalin, D-Penicillamine (2,5)-; D000109:Acetylcholine; D014287:Trimebutine; D009638:Norepinephrine