Kappa opioid receptor control of motivated behavior revisited

Since its discovery, the kappa opioid receptor (KOR) has held the curiosity of basic and clinical researchers across disciplines. Recent advances in technologies for measuring and manipulating KOR activity have poised the field for breakthrough discoveries. As paradigms shift, it is paramount that lessons from the foundational literature are synthesized and passed forward to inform future studies. At the same time, the promise of leveraging the KOR system to improve treatment of neuropsychiatric disorders has thus far failed to materialize, highlighting the need for critical evaluation of whether current frameworks have proven reliable and generalizable. To this end, we review the physiology and pharmacology of KORs and dynorphins and their role in motivated behavior from their discovery through present day. We focus on distinct epochs within the literature and, in parallel sections, present (A) a timeline of major findings leading to the frameworks on which current research is based, and (B) critically revisit the empirical support for specific aspects of these conclusions. In particular, we highlight discrepancies which subvert the canon that KORs' essential function is to encode negative affective states. By synthesizing the foundational literature and calling into question long-standing theories of KOR function, we hope to highlight the ideas that should remain foundational moving forward and identify areas that may benefit from reconceptualization.