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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Evidence for a 7-Benzylidenenaltrexone-Preferring Opioid Receptor Mediating the Inhibitory Actions of Peptidic δ- and μ-Opioid Agonists on Neurogenic Ion Transport in Porcine Ileal Mucosa

Sutthasinee Poonyachoti, Philip S. Portoghese and David R. Brown
Journal of Pharmacology and Experimental Therapeutics May 2001, 297 (2) 672-679;
Sutthasinee Poonyachoti
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Philip S. Portoghese
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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 (pIC50 = 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) (pIC50 = 8.0 ± 0.1), endomorphin I, and PL-017 inhibited short-circuit 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 antagonistd-Phe-Cys-Tyr-d-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.

Footnotes

  • Send reprint requests to: David R. Brown, Ph.D., Department of Veterinary PathoBiology, University of Minnesota, 1988 Fitch Ave., St. Paul, MN 55108-6010. E-mail:brown013{at}tc.umn.edu

  • This investigation was supported by National Institutes of Health Grant R01 DA-10200 to D.R.B. and R01 DA-01533 to P.S.P. S.P. was supported by a Royal Thai Government scholarship.

  • Abbreviations:
    OR
    opioid receptor
    DADLE
    [d-Ala2,d-Leu5]-enkephalin
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    DSLET
    [d-Ser2,Leu5,Thr6]-enkephalin
    DAMGO
    [d-Ala2,N-methyl-Phe4,Gly5-ol]-enkephalin
    PL-017
    [methyl-Phe3,d-Pro4]morphiceptin
    TIPP
    Tyr-1,2,3,4-tetrahydroisoquinoline-Phe-Phe-OH
    CTOP
    d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH2
    SNC80
    (+)-4-[(αR)-α(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl-3-methoxybenzyl)-N,N-diethylbenzamide
    U-50,488H
    trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]cyclohexyl) benzene-acetamide methanesulfonate
    U-69,593
    (5α,7α,8β)-(+)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)]-benzeneacetamide
    NTB
    naltriben
    BNTX
    7-benzylidenenaltrexone
    BSINTX
    7-(5′,6′-benzo-2′-spiro-indanyl)naltrexone
    Isc
    short-circuit current
    Gt
    tissue electrical conductance
    ETS
    electrical transmural stimulation
    PBS
    phosphate-buffered saline
    • Received September 19, 2000.
    • Accepted January 17, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 297 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 297, Issue 2
1 May 2001
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Evidence for a 7-Benzylidenenaltrexone-Preferring Opioid Receptor Mediating the Inhibitory Actions of Peptidic δ- and μ-Opioid Agonists on Neurogenic Ion Transport in Porcine Ileal Mucosa

Sutthasinee Poonyachoti, Philip S. Portoghese and David R. Brown
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 672-679;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Pharmacological Evidence for a 7-Benzylidenenaltrexone-Preferring Opioid Receptor Mediating the Inhibitory Actions of Peptidic δ- and μ-Opioid Agonists on Neurogenic Ion Transport in Porcine Ileal Mucosa

Sutthasinee Poonyachoti, Philip S. Portoghese and David R. Brown
Journal of Pharmacology and Experimental Therapeutics May 1, 2001, 297 (2) 672-679;
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