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<p>The κ-opioid receptor (KOR) is a key component of the opioid receptor system and belongs to the G protein-coupled receptor family. It is widely distributed in regions such as the mesolimbic system, amygdala and spinal cord, playing a central role in regulating depression, anxiety, drug addiction, and stress responses. While KOR agonists exhibit analgesic effects, they exacerbate negative emotions; conversely, KOR antagonists demonstrate significant potential in the treatment of neuropsychiatric disorders. This review examines the mechanisms of action and clinical translation progress of KOR antagonists, which improve disease phenotypes through mechanisms such as reversing dopamine inhibition, restoring glutamate/gamma-aminobutyric acid balance, and regulating the hypothalamic–pituitary–adrenal axis; they are categorized into three types based on duration of action. Current research focuses on antidepressant, anti-addiction, and stress regulation applications. The paper analyzes bottlenecks such as insufficient receptor selectivity and gender-dose differences, and outlines development strategies for highly selective ligands. Overall, this review synthesizes the molecular mechanisms of blockers, their applications in neuropsychiatric disorders, and clinical research progress.</p>

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Kappa opioid receptor antagonism in neuropsychiatry: from molecular mechanisms to clinical prospects

  • 期刊论文

  • 发表日期：

    2026年3月30日

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  • Hongyang Wang,
  • Yawei Ji,
  • Jingyao Huang,
  • Siqi Yang,
  • Qi Zhang,
  • Suwan Hu,
  • Xiangqing Xu,
  • Chun Yang

摘要

The κ-opioid receptor (KOR) is a key component of the opioid receptor system and belongs to the G protein-coupled receptor family. It is widely distributed in regions such as the mesolimbic system, amygdala and spinal cord, playing a central role in regulating depression, anxiety, drug addiction, and stress responses. While KOR agonists exhibit analgesic effects, they exacerbate negative emotions; conversely, KOR antagonists demonstrate significant potential in the treatment of neuropsychiatric disorders. This review examines the mechanisms of action and clinical translation progress of KOR antagonists, which improve disease phenotypes through mechanisms such as reversing dopamine inhibition, restoring glutamate/gamma-aminobutyric acid balance, and regulating the hypothalamic–pituitary–adrenal axis; they are categorized into three types based on duration of action. Current research focuses on antidepressant, anti-addiction, and stress regulation applications. The paper analyzes bottlenecks such as insufficient receptor selectivity and gender-dose differences, and outlines development strategies for highly selective ligands. Overall, this review synthesizes the molecular mechanisms of blockers, their applications in neuropsychiatric disorders, and clinical research progress.