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Research ArticleArticle

Short-Term Inverse-Agonist Treatment Induces Reciprocal Changes in δ-Opioid Agonist and Inverse-Agonist Binding Capacity

Graciela Piñeyro, Mounia Azzi, André De Léan, Peter Schiller and Michel Bouvier
Molecular Pharmacology October 2001, 60 (4) 816-827;
Graciela Piñeyro
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Mounia Azzi
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André De Léan
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Peter Schiller
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Michel Bouvier
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Abstract

This study assessed the effects of short-term treatment (30-min) with inverse agonists on receptor protein levels and on the ability of agonists, inverse agonists, and neutral antagonists to bind to the human δ-opioid receptor (hδOR). Incubation of human embryonic kidney 293s cells stably expressing hδOR with the inverse agonist ICI174864 (1 μM) induced reciprocal changes in agonist and inverse-agonist binding. The total number of binding sites recognized by the agonists [3H]bremazocine and [3H][d-Pen2,d-Pen5]-enkephalin was reduced by 33 and 57%, respectively, whereas binding capacity for the radiolabeled inverse-agonist [3H]Tyr-TicY[CH2NH]Cha-Phe-OH increased by 44%. In contrast, total receptor protein and sites labeled by neutral antagonists [3H]naltrindole and [3H]Tyr-d-Tic-Phe-Phe-OH remained unchanged. Pertussis toxin (PTX) and 5-guanylylimidodiphosphate (GppNHp) mimicked the outcome of ICI174864 pretreatment in promoting the loss of agonist binding sites. The lack of an additive effect on [3H]bremazocine binding when these three agents were combined indicates that inverse agonists may, in part, share the mechanism by which GppNHp and PTX reduce agonist binding capacity. Spontaneous recovery of maximal agonist binding capacity after inverse-agonist treatment was slow, suggesting a decrease in the isomerization rate between agonist- and inverse agonist–preferring conformations. Overall, the data presented are consistent with the idea that hδORs exist in multiple states capable of discriminating among ligands of different levels of efficacy and show that, after short-term treatment with an inverse agonist, the receptor ability to adopt conformations preferentially induced by agonist ligands is reduced.

Footnotes

  • G.P. was supported by a Postdoctoral Fellowship of the Canadian Institutes of Health Research (CIHR), and M.A. was supported by a Postdoctoral Fellowship of the Heart and Stroke Foundation of Canada (HSFC). M.B. holds the Hans-Selye Chair of Molecular and Cell Biology. This project was supported by grants from CIHR and HSFC and Canadian Research Chair in Molecular Pharmacology.

  • Abbreviations:
    GPCRs
    G protein-coupled receptors
    R
    inactive receptor
    R*
    active receptor
    G
    G protein
    hδOR
    human δ-opioid receptor
    IBMX
    3-isobutyl-1-methylxanthine
    DPDPE
    [d-Pen2,d-Pen5]-enkephalin
    GppNHp
    5-guanylylimidodiphosphate
    TIPP
    Tyr-d-Tic-Phe-Phe-OH
    TICPψ
    Tyr-TicY [CH2NH]Cha-Phe-OH
    DMEM
    Dulbecco's modified Eagle's medium
    PBS
    phosphate-buffered saline
    ANOVA
    analysis of variance
    PTX
    pertussis toxin
    AR
    free receptor
    ARG
    coupled receptor
    M
    spontaneous interaction between R and G
    Kapp
    apparent dissociation constant
    • Received March 29, 2001.
    • Accepted July 10, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 60 (4)
Molecular Pharmacology
Vol. 60, Issue 4
1 Oct 2001
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Research ArticleArticle

Short-Term Inverse-Agonist Treatment Induces Reciprocal Changes in δ-Opioid Agonist and Inverse-Agonist Binding Capacity

Graciela Piñeyro, Mounia Azzi, André De Léan, Peter Schiller and Michel Bouvier
Molecular Pharmacology October 1, 2001, 60 (4) 816-827;

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Research ArticleArticle

Short-Term Inverse-Agonist Treatment Induces Reciprocal Changes in δ-Opioid Agonist and Inverse-Agonist Binding Capacity

Graciela Piñeyro, Mounia Azzi, André De Léan, Peter Schiller and Michel Bouvier
Molecular Pharmacology October 1, 2001, 60 (4) 816-827;
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