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Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands.
Neuropharmacology 2016; 105:434-442N

Abstract

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/β-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 β-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 β-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 β-arrestin 2 rather than G-protein efficacy.

Authors+Show Affiliations

Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy. Electronic address: chiara.ruzza@unife.it.Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States.Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

26867504

Citation

Asth, L, et al. "Beta-arrestin 2 Rather Than G Protein Efficacy Determines the Anxiolytic-versus Antidepressant-like Effects of Nociceptin/orphanin FQ Receptor Ligands." Neuropharmacology, vol. 105, 2016, pp. 434-442.
Asth L, Ruzza C, Malfacini D, et al. Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. Neuropharmacology. 2016;105:434-442.
Asth, L., Ruzza, C., Malfacini, D., Medeiros, I., Guerrini, R., Zaveri, N. T., ... Calo', G. (2016). Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. Neuropharmacology, 105, pp. 434-442. doi:10.1016/j.neuropharm.2016.02.003.
Asth L, et al. Beta-arrestin 2 Rather Than G Protein Efficacy Determines the Anxiolytic-versus Antidepressant-like Effects of Nociceptin/orphanin FQ Receptor Ligands. Neuropharmacology. 2016;105:434-442. PubMed PMID: 26867504.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands. AU - Asth,L, AU - Ruzza,C, AU - Malfacini,D, AU - Medeiros,I, AU - Guerrini,R, AU - Zaveri,N T, AU - Gavioli,E C, AU - Calo',G, Y1 - 2016/02/08/ PY - 2015/12/04/received PY - 2016/02/03/revised PY - 2016/02/04/accepted PY - 2016/2/13/entrez PY - 2016/2/13/pubmed PY - 2017/6/24/medline KW - Anxiety KW - BRET KW - Depression KW - Elevated plus maze KW - Forced swim test KW - G protein KW - Mouse KW - N/OFQ KW - N/OFQ (PubChem CID: 16131448) KW - NOP receptor partial agonist KW - SB-612111 (PubChem CID: 10047612) KW - UFP-101 (PubChem CID: 25081457) KW - β-arrestin SP - 434 EP - 442 JF - Neuropharmacology JO - Neuropharmacology VL - 105 N2 - 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/β-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 β-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 β-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 β-arrestin 2 rather than G-protein efficacy. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/26867504/Beta_arrestin_2_rather_than_G_protein_efficacy_determines_the_anxiolytic_versus_antidepressant_like_effects_of_nociceptin/orphanin_FQ_receptor_ligands_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(16)30038-7 DB - PRIME DP - Unbound Medicine ER -