A Systematic Review on the Kappa Opioid Receptor and Its Ligands: New Directions for the Treatment of Pain, Anxiety, Depression, and Drug Abuse

13 July 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Kappa opioid receptor (KOR) is a member of the opioid receptor system, the G protein-coupled receptors that are expressed throughout the peripheral and central nervous systems and play crucial roles in the modulation of antinociception and a variety of behavioral states like anxiety, depression, and drug abuse. KOR agonists are known to produce potent analgesic effects and have been employed clinically for the treatment of pain, while KOR antagonists have displayed efficacy in the treatment of anxiety and depression. This review summarizes the history, design strategy, discovery, and development of KOR ligands. KOR agonists are categorized into G protein-biased KOR agonists and β-arrestin recruitment-biased KOR agonists, based on their degrees of bias. Mechanisms and associated effects of the G protein signaling pathway and β-arrestin recruitment signaling pathway are also discussed. Meanwhile, KOR antagonists are categorized into three groups, long-acting, intermediate-acting, and short-acting, based on their durations of action. In addition, we have special sections for mixed KOR agonists and selective peripheral KOR agonists. Mechanisms of action and pharmacokinetic, pharmacodynamic, and behavioral studies for each of these categories are also discussed in this review.


Kappa opioid receptor
biased and unbiased
agonists and antagonists
anxiety and depression
drug abuse


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