Journal
ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, VOL 60
Volume 60, Issue -, Pages 615-636Publisher
ANNUAL REVIEWS
DOI: 10.1146/annurev-pharmtox-010919-023317
Keywords
stress; major depressive disorder; kappa opioid receptor antagonist; antidepressant
Categories
Funding
- US Public Health Service [R01 MH92412, R01 MH105623]
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Exposure to stressful stimuli activates kappa opioid receptor (KOR) signaling, a process known to produce aversion and dysphoria in humans and other species. This endogenous opioid system is dysregulated in stress-related disorders, specifically in major depressive disorder (MDD). These findings serve as the foundation for a growing interest in the therapeutic potential of KOR antagonists as novel antidepressants. In this review, data supporting the hypothesis of dysregulated KOR function in MDD are considered. The clinical data demonstrating the therapeutic efficacy and safety of selective and mixed opioid antagonists are then presented. Finally, the preclinical evidence illustrating the induction of behaviors relevant to the endophenotypes of MDD and KOR antagonist activity in stress-naive and stress-exposed animals is evaluated. Overall, this review highlights the emergent literature supporting the pursuit of KOR antagonists as novel therapeutics for MDD and other stress-related disorders.
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