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Research ArticleNEUROPHARMACOLOGY

[Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

Daniela Rizzi, Anna Rizzi, Raffaella Bigoni, Valeria Camarda, Giuliano Marzola, Remo Guerrini, Carmela De Risi, Domenico Regoli and Girolamo Calo'
Journal of Pharmacology and Experimental Therapeutics January 2002, 300 (1) 57-63; DOI: https://doi.org/10.1124/jpet.300.1.57
Daniela Rizzi
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Anna Rizzi
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Raffaella Bigoni
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Valeria Camarda
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Giuliano Marzola
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Remo Guerrini
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Carmela De Risi
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Domenico Regoli
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Girolamo Calo'
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Abstract

The nociceptin (NC)/orphanin FQ analog, [Arg14,Lys15]NC, has been recently demonstrated to behave as a potent agonist at the human recombinant NC receptors (OP4). In this study, we evaluated the pharmacological profile of [Arg14,Lys15]NC in vitro on the native OP4 receptors expressed in isolated tissues and in vivo in the locomotor activity and the tail-withdrawal assays in mice. On isolated tissues, [Arg14,Lys15]NC mimicked the effects of NC, showing similar maximal effects but higher potencies (17-fold in the mouse vas deferens, 10-fold in the rat vas deferens, and about 5-fold in the guinea pig ileum and mouse colon). In these preparations, the effects of [Arg14,Lys15]NC were not modified by 1 μM naloxone, although antagonized by the OP4 receptor antagonists [Nphe1]NC(1–13)NH2(pA 2 ≅ 6) and (±)trans-1-[1-cyclooctylmethyl-3hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) (pA 2 ≅ 8). In the rat vas deferens, a cocktail of peptidase inhibitors increased the maximal effects of NC, its analog, and the pEC50 of NC (by 4-fold); the potency of [Arg14,Lys15]NC was not significantly modified by peptidase inhibitors. In in vivo experiments, [Arg14,Lys15]NC mimicked the effects of NC, producing, after intracerebroventricular administration, pronociceptive effects in the tail-withdrawal assay and inhibiting the locomotor activity of the mice. In both assays, [Arg14,Lys15]NC was about 30-fold more potent than NC and produced longer lasting effects. Taken together, the present data demonstrate that [Arg14,Lys15]NC behaves as a highly potent agonist of the OP4 receptor and is able to produce long-lasting effects in vivo, compared with the natural ligand NC.

Footnotes

  • This work was supported financially by the Italian Ministry of the University (Cofin 1990, grant to D.R.) and by the University of Ferrara (60% grant to G.C.).

  • Abbreviations

    NC
    nociceptin
    J-113397
    (±)trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one
    ANOVA
    analysis of variance
    • Received July 9, 2001.
    • Accepted September 19, 2001.
    • The American Society for Pharmacology and Experimental Therapeutics
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    Journal of Pharmacology and Experimental Therapeutics: 300 (1)
    Journal of Pharmacology and Experimental Therapeutics
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    1 Jan 2002
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    Research ArticleNEUROPHARMACOLOGY

    [Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

    Daniela Rizzi, Anna Rizzi, Raffaella Bigoni, Valeria Camarda, Giuliano Marzola, Remo Guerrini, Carmela De Risi, Domenico Regoli and Girolamo Calo'
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 57-63; DOI: https://doi.org/10.1124/jpet.300.1.57

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    Research ArticleNEUROPHARMACOLOGY

    [Arg14,Lys15]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies

    Daniela Rizzi, Anna Rizzi, Raffaella Bigoni, Valeria Camarda, Giuliano Marzola, Remo Guerrini, Carmela De Risi, Domenico Regoli and Girolamo Calo'
    Journal of Pharmacology and Experimental Therapeutics January 1, 2002, 300 (1) 57-63; DOI: https://doi.org/10.1124/jpet.300.1.57
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