Major depressive disorder (MDD) is a heterogeneous clinical syndrome involving distinct pathological processes. Core features of MDD include anhedonia, reduced motivation, increased anxiety, negative affective bias, cognitive impairments, and dysregulated neuroplasticity mechanisms. There are multiple biological hypotheses related to MDD, including dysfunction of the opioid system. Although opium was abandoned as an antidepressant after the introduction of monoaminergic drugs, there has been renewed interest in targeting the opioid system for MDD. In this review, we discuss the preclinical support of this idea using a neurocircuitry- and molecular neuroplasticity-based approach. This article highlights how the opioid system potently modulates mesolimbic circuitry underlying motivation and reward processing, limbic circuitry underlying fear and anxiety responses, cortical and hippocampal circuitry underlying a variety of cognitive functions, as well as broad functional and structural plasticity mechanisms. Ultimately, a more thorough understanding of how the opioid system modulates these core functional domains may lead to novel treatment strategies and molecular targets in the treatment of MDD.

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抑郁症中神经回路的阿片受体调节：从临床前数据可以学到什么？

严重抑郁症（MDD）是一种异质性临床综合征，涉及不同的病理过程。MDD的核心特征包括躁狂症，动机降低，焦虑感增加，负性情感偏见，认知障碍和神经可塑性机制失调。有多种与MDD相关的生物学假设，包括阿片类药物系统功能障碍。尽管在引入单胺能药物后放弃了鸦片作为抗抑郁药，但人们对针对MDD的阿片类药物系统重新产生了兴趣。在这篇综述中，我们讨论了使用基于神经回路和分子神经可塑性的方法对这一想法的临床前支持。本文重点介绍了阿片类药物系统如何有效调节潜在的动机和奖励过程中的中脑边缘回路，恐惧和焦虑反应的基础是边缘循环，各种认知功能是基础的皮质和海马循环，以及广泛的功能和结构可塑性机制。最终，对阿片样物质系统如何调节这些核心功能域的更彻底的了解可能会导致MDD治疗中的新颖治疗策略和分子靶标。