Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics

Abstract

: Despite similar distribution patterns and intracellular events observed in the nociceptin/orphanin FQ peptide (NOP) receptor and other opioid receptors, NOP receptor activation displays unique pharmacological profiles. Several researchers have identified a variety of peptide and non-peptide ligands to determine the functional roles of NOP receptor activation and observed that NOP receptorrelated ligands exhibit pain modality-dependent pain processing. Importantly, NOP receptor activation results in anti-nociception and anti-hypersensitivity at the spinal and supraspinal levels regardless of the experimental settings in non-human primates (NHPs). Given that the NOP receptor agonists synergistically enhance mu-opioid peptide (MOP) receptor agonist-induced anti-nociception, it has been hypothesized that dual NOP and MOP receptor agonists may display promising functional properties as analgesics. Accumulating evidence indicates that the mixed NOP/opioid receptor agonists demonstrate favorable functional profiles. In NHP studies, bifunctional NOP/MOP partial agonists (e.g., AT-121, BU08028, and BU10038) exerted potent anti-nociception via NOP and MOP receptor activation; however, dose-limiting adverse effects associated with the MOP receptor activation, including respiratory depression, itch sensation, physical dependence, and abuse liability, were not observed. Moreover, a mixed NOP/opioid receptor agonist, cebranopadol, presented promising outcomes in clinical trials as a novel analgesic. Collectively, the dual agonistic actions on NOP and MOP receptors, with appropriate binding affinities and efficacies, may be a viable strategy to develop innovative and safe analgesics.

Differential In Vitro Pharmacological Profiles of Structurally Diverse Nociceptin Receptor Agonists in Activating G Protein and Beta-Arrestin Signaling at the Human Nociceptin Opioid Receptor

“…In this study, we characterized the intrinsic activity of chemically diverse NOP agonists in various G protein-mediated functional assays (GTPγS binding, cAMP inhibition and GIRK activation) and characterized agonist-induced receptor trafficking by measuring ligand-induced NOP receptor phosphorylation of selected residues, arrestin recruitment and receptor internalization. Targeting the NOP receptor has been proposed by us and others as an approach to reduce the side effects of MOR agonists (Bird and Lambert, 2015;Gunther et al, 2018;Kiguchi et al, 2020a;Kiguchi et al, 2020b;Toll et al, 2009). Using an array of ligands, we showed that NOP agonists with varying functional selectivity towards the MOR receptor, i.e.…”

Potential innovative targets in the treatment of pain: Combined μ and NOP receptor agonists

“…10 The NOP receptor shares approximately 60 percent homology in the structural components of classical opioid (MOP, DOP, and KOP) receptors. 11,12 Unlike classical opioid receptors, the NOP receptor possesses little or no affinity for opioid peptides, eg, β-endorphin and enkephalin, or morphine-like compounds. One year after the identification of the NOP receptor, the natural ligand for NOP receptor was identified.…”

“…The activated NOP receptor couples to Gi/o-proteins to inhibit adenylate cyclase, decreasing Ca 2+ conductance and increasing K + conductance, among other intracellular processes. 11,12 Once activated, NOP receptors reduce afferent neuronal excitability and thereby modulate neurotransmitter release from axon terminals, including γ-amino butyric acid, glutamate, dopamine, and norepinephrine.…”

“…11 The NOP receptor is abundantly present within pain processing pathways such as the dorsal root ganglion; spinal dorsal horn; and periaqueductal gray area, thalamus, and rostro-ventral medulla within the brain. 12 Therefore, the activation of NOP receptors is likely to influence pain transmission. 13 The NOP and classical opioid receptors are not colocalized on the same neurons, but seem to exert their influences in partly distinct neural pathways.…”

“…Furthermore, NOP agonists did not induce side effects encountered with conventional analgesics, including respiratory depression, itching, or motor impairments. 12,17,24 When coadministered with opioid analgesics, NOP agonists ameliorated opioid-related side effects. 20,25,26 In fact, agents acting on NOP and MOP activation demonstrated a limited respiratory depression (or ceiling effect).…”