Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands

NEUROPHARMACOLOGY

卷:105

Article

Asth, L.¹  Ruzza, C.^2,3  Malfacini, D.^2,3  Medeiros, I.¹  Guerrini, R.^4,5  Zaveri, N. T.⁶  Gavioli, E. C.¹  Cabo, G.^2,3 

[1] Univ Fed Rio Grande do Norte, Dept Biophys & Pharmacol, BR-59072970 Natal, RN, Brazil

[2] Univ Ferrara, Dept Med Sci, Pharmacol Sect, I-44121 Ferrara, Italy

[3] Univ Ferrara, Natl Inst Neurosci, I-44121 Ferrara, Italy

[4] Univ Ferrara, Dept Chem & Pharmaceut Sci, I-44121 Ferrara, Italy

[5] Univ Ferrara, LTTA, I-44121 Ferrara, Italy

[6] Astraea Therapeut LLC, 320 Logue Ave, Mountain View, CA 94043 USA

关键词: N/OFQ;    Anxiety;    Depression;    G protein;    beta-arrestin;    NOP receptor partial agonist;    BRET;    Elevated plus maze;    Forced swim test;    Mouse;   

DOI  :  10.1016/j.neuropharm.2016.02.003

来源: Elsevier

【 摘 要 】

Background and purpose: Nociceptin/orphanin FQ (N/OFQ) receptor (NOP) agonists produce anxiolytic-like effects in rodents while antagonists promote antidepressant-like effects. The aim of this study was to investigate the effect on anxiety and depression of NOP receptor partial agonists such as the peptides [F/G]N/OFQ(1-13)NH2 and UFP-113 and the non-peptide AT-090. Experimental approach: In vitro AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 were tested for their ability to promote NOP/G-protein and NOP/beta-arrestin 2 interaction, using a bioluminescence resonance energy transfer assay. In vivo, they were tested in mice in the elevated plus maze (EPM) and in the forced swim (FST) tests. NOP partial agonists effects were systematically compared to those of full agonists (N/OFQ and Ro 65-6570) and antagonists (UFP-101 and SB-612111). Key results: In vitro, AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH2 promoted NOP/G protein interaction, with maximal effects lower than those evoked by N/OFQ and Ro 65-6570. AT-090 behaved as a NOP partial agonist also in inducing beta-arrestin 2 recruitment, while UFP-113 and [F/G]N/OFQ(1-13)NH2 were inactive in this assay. In vivo, AT-090 induced anxiolytic-like effects in the EPM but was inactive in the FST. Opposite results were obtained with UFP-113 and [F/G]N/OFQ(1-13)NH2. Conclusions and implications: NOP ligands producing similar effects on NOP/G protein interaction (partial agonism) but showing different effects on beta-arrestin 2 recruitment (partial agonism vs antagonism) elicited different actions on anxiety and mood. These results suggest that the action of a NOP ligand on emotional states is better predicted based on its beta-arrestin 2 rather than G-protein efficacy. (C) 2016 Elsevier Ltd. All rights reserved.

【 授权许可】

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