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Role of kappa-opioid receptors in stress and anxiety-related behavior

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Abstract

Rationale

Accumulating evidence indicates that brain kappa-opioid receptors (KORs) and dynorphin, the endogenous ligand that binds at these receptors, are involved in regulating states of motivation and emotion. These findings have stimulated interest in the development of KOR-targeted ligands as therapeutic agents. As one example, it has been suggested that KOR antagonists might have a wide range of indications, including the treatment of depressive, anxiety, and addictive disorders, as well as conditions characterized by co-morbidity of these disorders (e.g., post-traumatic stress disorder) A general effect of reducing the impact of stress may explain how KOR antagonists can have efficacy in such a variety of animal models that would appear to represent different disease states.

Objective

Here, we review evidence that disruption of KOR function attenuates prominent effects of stress. We will describe behavioral and molecular endpoints including those from studies that characterize the effects of KOR antagonists and KOR ablation on the effects of stress itself, as well as on the effects of exogenously delivered corticotropin-releasing factor, a brain peptide that mediates key effects of stress.

Conclusion

Collectively, available data suggest that KOR disruption produces anti-stress effects and under some conditions can prevent the development of stress-induced adaptations. As such, KOR antagonists may have unique potential as therapeutic agents for the treatment and even prevention of stress-related psychiatric illness, a therapeutic niche that is currently unfilled.

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Acknowledgments

This review represents an update on work described in the 2005 Jacob P. Waletzky Memorial Lecture, entitled “Experience-dependent alterations in the function of brain reward systems: the role of CREB” (WAC). The generosity of Dr. Jeremy Waletzky and his family is gratefully acknowledged.

Funding and disclosures

This research was supported by a National Defense Science and Engineering Graduate Fellowship (to AVV) and MH062366 (to WAC). Dr. Carlezon has a US patent covering the use of kappa antagonists in the treatment of depressive disorders (Assignee: McLean Hospital). In the last 3 years, Dr. Carlezon has received compensation for professional services from The American College of Neuropsychopharmacology and Concert Pharmaceuticals.

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Van’t Veer, A., Carlezon, W.A. Role of kappa-opioid receptors in stress and anxiety-related behavior. Psychopharmacology 229, 435–452 (2013). https://doi.org/10.1007/s00213-013-3195-5

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