Title:Nociceptin/Orphanin FQ Peptide Receptor-Related Ligands as Novel Analgesics
Volume: 20
Issue: 31
Author(s): Norikazu Kiguchi*, Huiping Ding, Shiroh Kishioka and Mei-Chuan Ko
Affiliation:
- Department of Pharmacology, Wakayama Medical University, Wakayama,Japan
Keywords:
Anti-nociception, Bifunctional ligand, Non-human primate, NOP receptor, MOP receptor, Peptide ligand, Nonpeptide
ligand, Spinal cord.
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 nonpeptide
ligands to determine the functional roles of NOP receptor activation and observed that NOP receptor-
related 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.