Abstract
Nociceptin/orphanin FQ controls several functions, including pain transmission, via stimulation of the N/OFQ peptide (NOP) receptor. Here we tested the hypothesis that NOP biased agonism may be instrumental for identifying innovative analgesics. In vitro experiments were performed with the dynamic mass redistribution label free assay and the NOP non-peptide agonists Ro 65-6570, AT-403 and MCOPPB. In vivo studies were performed in wild type and β-arrestin 2 knockout mice using the formalin, rotarod and locomotor activity tests. In vitro all compounds mimicked the effects of N/OFQ behaving as potent NOP full agonists. In vivo Ro 65-6570 demonstrated a slightly higher therapeutic index (antinociceptive vs. motor impairment effects) in knockout mice. However, all NOP agonists displayed very similar therapeutic index in normal mice despite significant differences in G protein biased agonism. In conclusion the different ability of inducing G protein vs. β-arrestin 2 recruitment of a NOP agonist cannot be applied to predict its antinociceptive vs. motor impairment properties.
Highlights
The peptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor (Meunier et al, 1995; Reinscheid et al, 1995)
The aim of the present study was to investigate the in vivo impact of NOP receptor functional selectivity; in particular we tested the hypothesis that NOP biased agonism may be instrumental for identifying effective analgesics devoid of the locomotor impairing effects associated with NOP activation
100 nM N/OFQ did not elicit any effect in Chinese Hamster Ovary (CHO) wild type cells and similar results were obtained for MCOPPB, Ro 65-6570, and AT-403 tested at the same concentration
Summary
The peptide nociceptin/orphanin FQ (N/OFQ) is the endogenous ligand of the N/OFQ peptide (NOP) receptor (Meunier et al, 1995; Reinscheid et al, 1995). The N/OFQ-NOP receptor system regulates several biological functions, including pain transmission, locomotor activity, memory, emotional states, food intake, drug abuse, micturition, cough reflexes, cardiovascular, respiratory, and immune functions (Lambert, 2008; Toll et al, 2016). The NOP receptor represents an innovative pharmacological target for the treatment of several conditions, including pain (Schröder et al, 2014; Calo and Lambert, 2018), depression (Gavioli and Calo’, 2013), drug addiction (Ciccocioppo et al, 2019), Parkinson’s disease (Mercatelli et al, 2020), and incontinence due to overactive bladder (Angelico et al, 2019). The pleiotropic effects exerted by N/OFQ and NOP ligands may limit their drug development. The sedative effects associated with high doses of NOP agonists hampered their development as antitussives. We hypothesized that one way to trigger some of the NOP mediated effects instead of others, might be the so-called functional selectivity of NOP agonists
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