Asth L, Ruzza C, Malfacini D, Medeiros I, Guerrini R, Zaveri N T, Gavioli E C, Calo' G
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.
Neuropharmacology. 2016 Jun;105:434-442. doi: 10.1016/j.neuropharm.2016.02.003. Epub 2016 Feb 8.
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.
痛敏肽/孤啡肽FQ（N/OFQ）受体（NOP）激动剂在啮齿动物中产生抗焦虑样作用，而拮抗剂则促进抗抑郁样作用。本研究的目的是研究NOP受体部分激动剂，如肽类[F/G]N/OFQ(1 - 13)NH2和UFP - 113以及非肽类AT - 090对焦虑和抑郁的影响。
使用生物发光共振能量转移测定法，在体外测试AT - 090、UFP - 113和[F/G]N/OFQ(1 - 13)NH2促进NOP/G蛋白和NOP/β - 抑制蛋白2相互作用的能力。在体内，在高架十字迷宫（EPM）和强迫游泳（FST）试验中对小鼠进行测试。将NOP部分激动剂的作用与完全激动剂（N/OFQ和Ro 65 - 6570）和拮抗剂（UFP - 101和SB - 612111）的作用进行系统比较。
在体外，AT - 090、UFP - 113和[F/G]N/OFQ(1 - 13)NH2促进NOP/G蛋白相互作用，其最大效应低于N/OFQ和Ro 65 - 6570所引起的效应。在诱导β - 抑制蛋白2募集方面，AT - 090也表现为NOP部分激动剂，而UFP - 113和[F/G]N/OFQ(1 - 13)NH2在该测定中无活性。在体内，AT - 090在EPM中诱导抗焦虑样作用，但在FST中无活性。UFP - 113和[F/G]N/OFQ(1 - 13)NH2则得到相反的结果。
对NOP/G蛋白相互作用产生相似效应（部分激动作用）但对β - 抑制蛋白2募集表现出不同效应（部分激动作用与拮抗作用）的NOP配体，对焦虑和情绪产生不同的作用。这些结果表明，基于其对β - 抑制蛋白2而非G蛋白的效能，能更好地预测NOP配体对情绪状态的作用。
