Kappa Opioid Receptors Revealed: Disentangling the Pharmacology to Open Up New Therapeutic Strategies

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Background

The kappa opioid receptor (KOR) and its endogenous ligands, the dynorphins, are expressed both in the central and peripheral nervous systems. The modulation of this G protein-coupled receptor plays a key role in a wide array of physiological functions. As such, it is also inevitably involved in numerous and diverse neurologic and psychiatric diseases. This fostered the still ongoing intense research on ligands for KOR. However, studies have been complicated by the close homology among opioid receptor isoforms. The KOR ligands synthetized so far have distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists (the last with both long and short half-lives). The agonism to KOR can induce different signaling cascades inside the targeted cell, being a G-coupled receptor. Also, most of the knowledge we have accumulated so far on KOR blockade is based on studies employing drugs with unusual and unclear pharmacokinetics. All these complicate both the interpretation of results obtained with different ligands as well as the translation of preclinical findings into the clinic. Further understanding of the molecular pharmacology of KOR is essential for future advancement in the field.



The plethora of drugs synthetized that can modulate the KOR signaling is invaluable to unveil the complex pharmacology of this receptor. Some of them could also represent a promising strategy for developing therapeutics for several human diseases, including depression, addiction, anxiety, and pain. Some molecules reached the clinical trial phase, but no KOR ligand has been approved for therapy yet. Thus, more research effort is needed to understand if and how KOR modulation could be therapeutically relevant. We already know that KOR-mediated signaling regulates many aspects of the mesocorticolimbic dopamine system, contributing to negative affective states, which are common symptoms for a variety of neuropsychiatric disorders. As such, a deep understanding of how dynorphins/KOR signaling modulates neurotransmission in different brain areas and affect behaviors could be valuable to help clinicians translate this new knowledge into therapy. The huge technical advancements we have seen in recent years could help to reach this goal.



This Research Topic aims to feature articles clarifying the pharmacology of the KOR system. We seek novel findings encompassing the role of dynorphins and KOR in neuropsychiatric disorders as well as dissecting the function of the dynorphin/KOR system in shaping both dopamine and non-dopamine neurotransmission.

This Research Topic welcomes original articles and review papers on the following themes, but is not limited to them:

• Studies elucidating the pharmacology of ligands to KOR, as agonists, antagonists, partial agonists and biased agonists.

• The role of dynorphins and KOR in reward, stress and negative affective states and the impact of their modulation in pain, addiction, and other neuropsychiatric diseases.

• Pharmacological, chemogenetic, or optogenetic approaches aimed at dissecting KOR-mediated brain signaling as well as regional dynorphins release and functions.

• The diverse cell signaling cascades activated by KOR agonism.

• The involvement of KOR in both dopamine and non-dopamine neuronal transmission and its role in behaviors, cognition, pain perception, motivation, and emotions.

• Sex differences in KOR-mediated behavior and their implication in neuropsychiatric disorders

Keywords: KOR, KOP, dynorphins, KOP agonist, KOP antagonist, partial agonist, G-protein coupled receptors, beta-arrestin, addiction, pain

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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