Role of peripheral mu, delta and kappa opioid receptors in opioid-induced inhibition of gastrointestinal transit in rats

A. Tavani, P. Pertrillo, A. La Regina, M. Sbacchi

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Abstract

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 non-selective 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 efffects than to antagonize doses of morphine equiactive to DADLE on the gut. Linear dose-related inhibition of DADLE-induced constipation was obtained with the universal antagonist Mr 2266 at doses between 0.006 and 0.1 mg/kg i.p. The quaternary opioid antagonist N-methyl levallorphan (32 mg/kg s.c., 50 min before) fully prevented the inhibition of gastrointestinal transit induced by morphine and DAMGO at doses 10 to 40 times their A50. Intraperitoneal doses of morphine (2.5 mg/kg), DAMGO (1 mg/kg), DADLE (2 mg/kg) and DSLET (8 mg/kg) much higher than those used for gastrointestinal transit testeing did not delay the nociceptive response on the hot-plate (55°C) between 1 and 40 min after drug administration. Thus the inhibition of gastrointestinal transit in rats induced by locally injected opioids may depend mainly on the interaction of the agonists at peripheral mu receptors; the delta receptors appear to have only a secondary part, if any, and the kappa receptors seem to have no significant role.

Original languageEnglish
Pages (from-to)91-97
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume254
Issue number1
Publication statusPublished - 1990

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Gastrointestinal Transit
kappa Opioid Receptor
delta Opioid Receptor
mu Opioid Receptor
Opioid Analgesics
Morphine
Enkephalins
Naloxone
Levallorphan
Leucine-2-Alanine Enkephalin
D-Penicillamine (2,5)-Enkephalin
Ala(2)-enkephalinamide-met
Narcotic Antagonists
Charcoal
Opioid Receptors
Constipation
Meals

ASJC Scopus subject areas

  • Pharmacology

Cite this

Role of peripheral mu, delta and kappa opioid receptors in opioid-induced inhibition of gastrointestinal transit in rats. / Tavani, A.; Pertrillo, P.; La Regina, A.; Sbacchi, M.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 254, No. 1, 1990, p. 91-97.

Research output: Contribution to journalArticle

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abstract = "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 non-selective 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 efffects than to antagonize doses of morphine equiactive to DADLE on the gut. Linear dose-related inhibition of DADLE-induced constipation was obtained with the universal antagonist Mr 2266 at doses between 0.006 and 0.1 mg/kg i.p. The quaternary opioid antagonist N-methyl levallorphan (32 mg/kg s.c., 50 min before) fully prevented the inhibition of gastrointestinal transit induced by morphine and DAMGO at doses 10 to 40 times their A50. Intraperitoneal doses of morphine (2.5 mg/kg), DAMGO (1 mg/kg), DADLE (2 mg/kg) and DSLET (8 mg/kg) much higher than those used for gastrointestinal transit testeing did not delay the nociceptive response on the hot-plate (55°C) between 1 and 40 min after drug administration. Thus the inhibition of gastrointestinal transit in rats induced by locally injected opioids may depend mainly on the interaction of the agonists at peripheral mu receptors; the delta receptors appear to have only a secondary part, if any, and the kappa receptors seem to have no significant role.",
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N2 - 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 non-selective 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 efffects than to antagonize doses of morphine equiactive to DADLE on the gut. Linear dose-related inhibition of DADLE-induced constipation was obtained with the universal antagonist Mr 2266 at doses between 0.006 and 0.1 mg/kg i.p. The quaternary opioid antagonist N-methyl levallorphan (32 mg/kg s.c., 50 min before) fully prevented the inhibition of gastrointestinal transit induced by morphine and DAMGO at doses 10 to 40 times their A50. Intraperitoneal doses of morphine (2.5 mg/kg), DAMGO (1 mg/kg), DADLE (2 mg/kg) and DSLET (8 mg/kg) much higher than those used for gastrointestinal transit testeing did not delay the nociceptive response on the hot-plate (55°C) between 1 and 40 min after drug administration. Thus the inhibition of gastrointestinal transit in rats induced by locally injected opioids may depend mainly on the interaction of the agonists at peripheral mu receptors; the delta receptors appear to have only a secondary part, if any, and the kappa receptors seem to have no significant role.

AB - 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 non-selective 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 efffects than to antagonize doses of morphine equiactive to DADLE on the gut. Linear dose-related inhibition of DADLE-induced constipation was obtained with the universal antagonist Mr 2266 at doses between 0.006 and 0.1 mg/kg i.p. The quaternary opioid antagonist N-methyl levallorphan (32 mg/kg s.c., 50 min before) fully prevented the inhibition of gastrointestinal transit induced by morphine and DAMGO at doses 10 to 40 times their A50. Intraperitoneal doses of morphine (2.5 mg/kg), DAMGO (1 mg/kg), DADLE (2 mg/kg) and DSLET (8 mg/kg) much higher than those used for gastrointestinal transit testeing did not delay the nociceptive response on the hot-plate (55°C) between 1 and 40 min after drug administration. Thus the inhibition of gastrointestinal transit in rats induced by locally injected opioids may depend mainly on the interaction of the agonists at peripheral mu receptors; the delta receptors appear to have only a secondary part, if any, and the kappa receptors seem to have no significant role.

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