Pharmacological evidence for a 7-benzylidenenaltrexone-preferring opioid receptor mediating the inhibitory actions of peptidic δ7 and μ-opioid agonists on neurogenic ion transport in porcine ileal mucosa

Sutthasinee Poonyachoti, Philip S Portoghese, David R Brown

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Abstract

The antidiarrheal and constipating effects of opiates are partly attributed to reductions in active anion secretion across the intestinal mucosa that are modulated by submucosal neurons. In this study, the opioid receptor mediating the actions of opioids on ion transport was characterized in mucosa-submucosa sheets from porcine ileum. Electrical transmural stimulation evoked transient increases in short-circuit current, an electrical measure of neurogenic ion transport, in this preparation. After serosal addition, the peptidic δ-opioid agonists [D-Ala2]-deltorphin II (plC50 = 8.4 ± 0.7), [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Pen2,D-Pen5]-enkephalin (DPDPE), and [D-Ser2,Leu5,Thr6]-enkephalin (DSLET), and the μ-opioid agonists [D-Ala2,N-methyl-Phe4,Gly5-ol]-enkephalin (DAMGO) (plC50 = 8.0 ± 0.1), endomorphin I, and PL-017 inhibited shortcircuit current elevations. Nonpeptidic μ- or δ-opioid agonists (morphine, loperamide, and SNC80) and κ-opioid agonists (U-50,488H and U-69,593) were <360-fold less potent than deltorphin II. At 100 nM, the δ1-opioid antagonist 7-benzylidenenaltrexone reduced the potencies of DPDPE and DAMGO by 13.5- and 15.5-fold, respectively; at an identical concentration naltriben, a δ2-opioid antagonist, or the μ-opioid antagonist D-Phe-Cys-TyrD-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) reduced DPDPE potency by 4.1- and 3.4-fold, respectively, but had no significant effect on DAMGO potency. Using primary antisera directed toward cloned opioid receptors, δ-opioid receptor immunoreactivity was immunohistochemically localized in submucosal neurons and nerve fibers, but immunoreactivities to κ- or μ-opioid receptors were not detected in the mucosa-submucosa. These results suggest that a novel 7-benzylidenenaltrexone-sensitive opioid receptor is expressed in submucosal neurons of the porcine ileum, which mediates the inhibitory effects of peptidic μ- and δ-opioid agonists on neurogenic ion transport.

Original languageEnglish (US)
Pages (from-to)672-679
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume297
Issue number2
StatePublished - May 8 2001

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D-Penicillamine (2,5)-Enkephalin
Ion Transport
Opioid Receptors
Opioid Analgesics
Mucous Membrane
Swine
Enkephalins
Pharmacology
Narcotic Antagonists
Ileum
Neurons
Opiate Alkaloids
(trans)-Isomer 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide
Loperamide
Antidiarrheals
Intestinal Mucosa
Nerve Fibers
Morphine
Electric Stimulation
Anions

Cite this

@article{bed5f05d7a514f9ca242e210f9c8f333,
title = "Pharmacological evidence for a 7-benzylidenenaltrexone-preferring opioid receptor mediating the inhibitory actions of peptidic δ7 and μ-opioid agonists on neurogenic ion transport in porcine ileal mucosa",
abstract = "The antidiarrheal and constipating effects of opiates are partly attributed to reductions in active anion secretion across the intestinal mucosa that are modulated by submucosal neurons. In this study, the opioid receptor mediating the actions of opioids on ion transport was characterized in mucosa-submucosa sheets from porcine ileum. Electrical transmural stimulation evoked transient increases in short-circuit current, an electrical measure of neurogenic ion transport, in this preparation. After serosal addition, the peptidic δ-opioid agonists [D-Ala2]-deltorphin II (plC50 = 8.4 ± 0.7), [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Pen2,D-Pen5]-enkephalin (DPDPE), and [D-Ser2,Leu5,Thr6]-enkephalin (DSLET), and the μ-opioid agonists [D-Ala2,N-methyl-Phe4,Gly5-ol]-enkephalin (DAMGO) (plC50 = 8.0 ± 0.1), endomorphin I, and PL-017 inhibited shortcircuit current elevations. Nonpeptidic μ- or δ-opioid agonists (morphine, loperamide, and SNC80) and κ-opioid agonists (U-50,488H and U-69,593) were <360-fold less potent than deltorphin II. At 100 nM, the δ1-opioid antagonist 7-benzylidenenaltrexone reduced the potencies of DPDPE and DAMGO by 13.5- and 15.5-fold, respectively; at an identical concentration naltriben, a δ2-opioid antagonist, or the μ-opioid antagonist D-Phe-Cys-TyrD-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) reduced DPDPE potency by 4.1- and 3.4-fold, respectively, but had no significant effect on DAMGO potency. Using primary antisera directed toward cloned opioid receptors, δ-opioid receptor immunoreactivity was immunohistochemically localized in submucosal neurons and nerve fibers, but immunoreactivities to κ- or μ-opioid receptors were not detected in the mucosa-submucosa. These results suggest that a novel 7-benzylidenenaltrexone-sensitive opioid receptor is expressed in submucosal neurons of the porcine ileum, which mediates the inhibitory effects of peptidic μ- and δ-opioid agonists on neurogenic ion transport.",
author = "Sutthasinee Poonyachoti and Portoghese, {Philip S} and Brown, {David R}",
year = "2001",
month = "5",
day = "8",
language = "English (US)",
volume = "297",
pages = "672--679",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

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TY - JOUR

T1 - Pharmacological evidence for a 7-benzylidenenaltrexone-preferring opioid receptor mediating the inhibitory actions of peptidic δ7 and μ-opioid agonists on neurogenic ion transport in porcine ileal mucosa

AU - Poonyachoti, Sutthasinee

AU - Portoghese, Philip S

AU - Brown, David R

PY - 2001/5/8

Y1 - 2001/5/8

N2 - The antidiarrheal and constipating effects of opiates are partly attributed to reductions in active anion secretion across the intestinal mucosa that are modulated by submucosal neurons. In this study, the opioid receptor mediating the actions of opioids on ion transport was characterized in mucosa-submucosa sheets from porcine ileum. Electrical transmural stimulation evoked transient increases in short-circuit current, an electrical measure of neurogenic ion transport, in this preparation. After serosal addition, the peptidic δ-opioid agonists [D-Ala2]-deltorphin II (plC50 = 8.4 ± 0.7), [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Pen2,D-Pen5]-enkephalin (DPDPE), and [D-Ser2,Leu5,Thr6]-enkephalin (DSLET), and the μ-opioid agonists [D-Ala2,N-methyl-Phe4,Gly5-ol]-enkephalin (DAMGO) (plC50 = 8.0 ± 0.1), endomorphin I, and PL-017 inhibited shortcircuit current elevations. Nonpeptidic μ- or δ-opioid agonists (morphine, loperamide, and SNC80) and κ-opioid agonists (U-50,488H and U-69,593) were <360-fold less potent than deltorphin II. At 100 nM, the δ1-opioid antagonist 7-benzylidenenaltrexone reduced the potencies of DPDPE and DAMGO by 13.5- and 15.5-fold, respectively; at an identical concentration naltriben, a δ2-opioid antagonist, or the μ-opioid antagonist D-Phe-Cys-TyrD-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) reduced DPDPE potency by 4.1- and 3.4-fold, respectively, but had no significant effect on DAMGO potency. Using primary antisera directed toward cloned opioid receptors, δ-opioid receptor immunoreactivity was immunohistochemically localized in submucosal neurons and nerve fibers, but immunoreactivities to κ- or μ-opioid receptors were not detected in the mucosa-submucosa. These results suggest that a novel 7-benzylidenenaltrexone-sensitive opioid receptor is expressed in submucosal neurons of the porcine ileum, which mediates the inhibitory effects of peptidic μ- and δ-opioid agonists on neurogenic ion transport.

AB - The antidiarrheal and constipating effects of opiates are partly attributed to reductions in active anion secretion across the intestinal mucosa that are modulated by submucosal neurons. In this study, the opioid receptor mediating the actions of opioids on ion transport was characterized in mucosa-submucosa sheets from porcine ileum. Electrical transmural stimulation evoked transient increases in short-circuit current, an electrical measure of neurogenic ion transport, in this preparation. After serosal addition, the peptidic δ-opioid agonists [D-Ala2]-deltorphin II (plC50 = 8.4 ± 0.7), [D-Ala2,D-Leu5]enkephalin (DADLE), [D-Pen2,D-Pen5]-enkephalin (DPDPE), and [D-Ser2,Leu5,Thr6]-enkephalin (DSLET), and the μ-opioid agonists [D-Ala2,N-methyl-Phe4,Gly5-ol]-enkephalin (DAMGO) (plC50 = 8.0 ± 0.1), endomorphin I, and PL-017 inhibited shortcircuit current elevations. Nonpeptidic μ- or δ-opioid agonists (morphine, loperamide, and SNC80) and κ-opioid agonists (U-50,488H and U-69,593) were <360-fold less potent than deltorphin II. At 100 nM, the δ1-opioid antagonist 7-benzylidenenaltrexone reduced the potencies of DPDPE and DAMGO by 13.5- and 15.5-fold, respectively; at an identical concentration naltriben, a δ2-opioid antagonist, or the μ-opioid antagonist D-Phe-Cys-TyrD-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) reduced DPDPE potency by 4.1- and 3.4-fold, respectively, but had no significant effect on DAMGO potency. Using primary antisera directed toward cloned opioid receptors, δ-opioid receptor immunoreactivity was immunohistochemically localized in submucosal neurons and nerve fibers, but immunoreactivities to κ- or μ-opioid receptors were not detected in the mucosa-submucosa. These results suggest that a novel 7-benzylidenenaltrexone-sensitive opioid receptor is expressed in submucosal neurons of the porcine ileum, which mediates the inhibitory effects of peptidic μ- and δ-opioid agonists on neurogenic ion transport.

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VL - 297

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EP - 679

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

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