title: Beta-arrestin 2 rather than G protein efficacy determines the anxiolytic-versus antidepressant-like effects of nociceptin/orphanin FQ receptor ligands.
abstract: 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.
  
  
  
  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).
  
  
  
  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.
  
  
  
  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: Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.
authors: L
authors: L
authors: Asth
authors: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy. Electronic address: chiara.ruzza@unife.it.
authors: C
authors: C
authors: Ruzza
authors: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors: D
authors: D
authors: Malfacini
authors: Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.
authors: I
authors: I
authors: Medeiros
authors: Department of Chemical and Pharmaceutical Sciences and LTTA, University of Ferrara, 44121 Ferrara, Italy.
authors: R
authors: R
authors: Guerrini
authors: Astraea Therapeutics, LLC., 320 Logue Avenue, Mountain View, CA 94043, United States.
authors: N T
authors: NT
authors: Zaveri
authors: Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.
authors: E C
authors: EC
authors: Gavioli
authors: Department of Medical Sciences, Section of Pharmacology and National Institute of Neuroscience, University of Ferrara, 44121 Ferrara, Italy.
authors: G
authors: G
authors: Calo'
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D003508:Cycloheptanes / Q000494:pharmacology; D004644:Emotions / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D010880:Piperidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology; D013550:Swimming / Q000523:psychology; D000071560:beta-Arrestin 2 / Q000819:agonists / Q000378:metabolism*; D000094942:Nociceptin Receptor
chemical_list: C121726:8-acenaphthen-1-yl-1-phenyl-1,3,8-triazaspiro(4.5)decan-4-one; D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003508:Cycloheptanes; D007093:Imidazoles; D008024:Ligands; D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000071560:beta-Arrestin 2; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D019204:GTP-Binding Proteins; D000094942:Nociceptin Receptor
keywords: Anxiety; BRET; Depression; Elevated plus maze; Forced swim test; G protein; Mouse; N/OFQ; N/OFQ (PubChem CID: 16131448); NOP receptor partial agonist; SB-612111 (PubChem CID: 10047612); UFP-101 (PubChem CID: 25081457); β-arrestin