Role of peripheral mu, delta and kappa opioid receptors in opioid-induced inhibition of gastrointestinal transit in rats.
The roles of various types of opioid receptors in opioid-induced local inhibition of gastrointestinal transit were studied in rats 5 min after a charcoal meal, injecting i.p. relatively selective agonists and antagonists. The proposed mu agonists, morphine and [D-Ala2,MePhe4,Gly-ol5]enkephalin (DAMGO), and the nonselective delta agonist, [D-Ala2,D-Leu5]enkephalin (DADLE), produced a dose-related inhibition of gastrointestinal transit at the peak time and the i.p. doses producing a 50% reduction of the control values (A50) were 0.015, 0.006 and 0.023 mg/kg, respectively, for morphine, DAMGO and DADLE. The effect of the other nonselective delta agonist, [D-Ser2,L-Leu5]enkephalyl-Thr (DSLET), was not linearly related with the dose. The proposed selective delta agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), and the selective kappa agonist, U-69,593, up to 2 and 15 mg/kg i.p., respectively, did not delay gastrointestinal transit. Naloxone (0.05 mg/kg i.p.) injected 1 min before each agonist produced a significant parallel shift to the right of the dose-response curves for morphine and DAMGO, but only partly antagonized the effects of DADLE and DSLET. The selective delta antagonist ICI 174,864 (1 mg/kg i.p., injected 1 min before each agonist) shifted the dose-response curve of DADLE, but not of the mu agonists, slightly, but significantly to the right, and had an inconsistent effect on DSLET. Naloxone prevented DADLE's effect on the gut with a nonlinear dose-response curve and much higher doses of naloxone were required to prevent fully DADLE-induced effects than to antagonize doses of morphine equiactive to DADLE on the gut.(ABSTRACT TRUNCATED AT 250 WORDS)
Tavani
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Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Petrillo
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La Regina
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Sbacchi
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M
D000818:Animals; D004723:Endorphins / Q000494:pharmacology*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D016308:Enkephalin, Leucine-2-Alanine; D004745:Enkephalins / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000502:physiology*; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu
D004723:Endorphins; D004745:Enkephalins; D009842:Oligopeptides; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004743:Enkephalin, Leucine; D016308:Enkephalin, Leucine-2-Alanine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; C040643:N,N-diallyl-tyrosyl-alpha-aminoisobutyric acid-phenylalanyl-leucine