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

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)NH 2 and UFP-113 and the non-peptide AT-090.Experimental approach-In vitro AT-090, UFP-113, and [F/G]N/OFQ(1-13)NH 2 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). Authorship contribution statement LA, CR, ECG, and GC designed research; LA, CR, DM, and IUM performed the experiments; NTZ and RG contributed unpublished reagents/analytic tools; LA, CR, and DM analyzed data; LA, CR, ECG and GC wrote the paper. 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. Conflicts of interest HHS Public Access

In vitro functional characterization of novel nociceptin/orphanin FQ receptor agonists in recombinant and native preparations

“…In fact several in vivo actions of Ro 64-6198 and Ro 65-6570 were sensitive to NOP antagonists and no longer evident in NOP(−/−) animals (reviewed in Toll et al (2016)). In addition we recently demonstrated that the anxiolytic-like effect of AT-090 in the mouse elevated plus maze can be detected in NOP(+/+) but not NOP(−/−) mice (Asth et al, 2016). …”

“…Selective NOP antagonists have been investigated as antidepressants (Gavioli and Calo, 2013; Post et al, 2016) and for Parkinson’s disease treatment (Marti et al, 2013, 2004, 2010) whereas selective nonpeptide NOP agonists have shown significant efficacy for anxiety (Gavioli and Calo, 2006; Shoblock, 2007; Witkin et al, 2014) and pain (Schroder et al, 2014; Toll et al, 2016). Recently, NOP receptor partial agonists have also been developed and investigated in models of anxiety and depression (Asth et al, 2016; Ross et al, 2015). …”

In vitro pharmacological characterization of a novel unbiased NOP receptor‐selective nonpeptide agonist AT‐403

“…) and used for characterizing the functional selectivity of novel NOP compounds (Asth et al. ; Bird et al. ; Rizzi et al.…”

Pharmacological studies on the NOP and opioid receptor agonist PWT2-[Dmt1]N/OFQ(1-13)

“…The BRET assay used to investigate the ability of [Dmt 1 ]N/OFQ(1-13)-NH 2 and PWT2-[Dmt 1 ] to promote receptor interaction with G protein and β-arrestin 2 has been previously validated for classical opioid (Molinari et al, 2010) as well as NOP receptors (Malfacini et al, 2015) and then used for characterizing novel ligands (Asth et al, 2016; Bird et al, 2016; Rizzi et al, 2016) or for selecting the best compounds for inducing receptor stability and crystallogenesis (Miller et al, 2015). In line with previous findings (Malfacini et al, 2015; Rizzi et al, 2016), the standard peptides N/OFQ and dermorphin behaved as potent and selective agonists in promoting receptor interaction both with G protein and β-arrestin 2.…”