An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects

Bibliographic Details
Title: An updated assessment of the translational promise of G-protein-biased kappa opioid receptor agonists to treat pain and other indications without debilitating adverse effects
Authors: Alexander R. French, Richard M. van Rijn
Source: Pharmacological Research, Vol 177, Iss , Pp 106091- (2022)
Publisher Information: Elsevier, 2022.
Publication Year: 2022
Collection: LCC:Therapeutics. Pharmacology
Subject Terms: Kappa opioid receptor, Biased agonism, Antinociception, Aversion, Sedation, Depression, Therapeutics. Pharmacology, RM1-950
More Details: Kappa opioid receptor (κOR) agonists lack the abuse liability and respiratory depression effects of clinically used mu opioid receptor (μOR) analgesics and are hypothesized to be safer alternatives. However, κOR agonists have limiting adverse effects of their own, including aversion, sedation, and mood effects, that have hampered their clinical translation. Studies performed over the last 15 years have suggested that these adverse effects could result from activation of distinct intracellular signaling pathways that are dependent on β-arrestin, whereas signaling downstream of G protein activation produces antinociception. This led to the hypothesis that agonists biased away from β-arrestin signaling would have improved therapeutic windows over traditional unbiased agonists and allow for clinical development of analgesic G-protein-biased κOR agonists. Given a recent controversy regarding the benefits of G-protein-biased μOR agonists, it is timely to reassess the therapeutic promise of G-protein-biased κOR agonists. Here we review recent discoveries from preclinical κOR studies and critically evaluate the therapeutic windows of G-protein-biased κOR agonists in each of the adverse effects above. Overall, we find that G-protein-biased κOR agonists generally have improved therapeutic window relative to unbiased agonists, although frequently study design limits strong conclusions in this regard. However, a steady flow of newly developed biased κOR agonists paired with recently engineered behavioral and molecular tools puts the κOR field in a prime position to make major advances in our understanding of κOR function and fulfill the promise of translating a new generation of biased κOR agonists to the clinic.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1096-1186
Relation: http://www.sciencedirect.com/science/article/pii/S1043661822000366; https://doaj.org/toc/1096-1186
DOI: 10.1016/j.phrs.2022.106091
Access URL: https://doaj.org/article/f4cae45bd8d543e78f83cd7f482312fd
Accession Number: edsdoj.f4cae45bd8d543e78f83cd7f482312fd
Database: Directory of Open Access Journals
More Details
ISSN:10961186
DOI:10.1016/j.phrs.2022.106091
Published in:Pharmacological Research
Language:English