UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA; Neuroscience Graduate Program, University of California, San Francisco, CA, USA.
UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, USA.
Neuropharmacology. 2023 Mar 1;225:109376. doi: 10.1016/j.neuropharm.2022.109376. Epub 2022 Dec 11.
The opioid G-protein coupled receptors (GPCRs) strongly modulate many of the central nervous system structures that contribute to neurological and psychiatric disorders including pain, major depressive disorder, and substance use disorders. To better treat these and related diseases, it is essential to understand the signaling of their endogenous ligands. In this review, we focus on what is known and unknown about the regulation of the over two dozen endogenous peptides with high affinity for one or more of the opioid receptors. We briefly describe which peptides are produced, with a particular focus on the recently proposed possible synthesis pathways for the endomorphins. Next, we describe examples of endogenous opioid peptide expression organization in several neural circuits and how they appear to be released from specific neural compartments that vary across brain regions. We discuss current knowledge regarding the strength of neural activity required to drive endogenous opioid peptide release, clues about how far peptides diffuse from release sites, and their extracellular lifetime after release. Finally, as a translational example, we discuss the mechanisms of action of naltrexone (NTX), which is used clinically to treat alcohol use disorder. NTX is a synthetic morphine analog that non-specifically antagonizes the action of most endogenous opioid peptides developed in the 1960s and FDA approved in the 1980s. We review recent studies clarifying the precise endogenous activity that NTX prevents. Together, the works described here highlight the challenges and opportunities the complex opioid system presents as a therapeutic target.
阿片类 G 蛋白偶联受体（GPCR）强烈调节许多参与神经和精神疾病的中枢神经系统结构，包括疼痛、重度抑郁症和物质使用障碍。为了更好地治疗这些疾病和相关疾病，了解其内源性配体的信号转导至关重要。在这篇综述中，我们重点介绍了关于具有高亲和力的二十多种内源性肽对阿片受体的调节的已知和未知内容。我们简要描述了哪些肽被产生，特别关注最近提出的内吗啡肽的可能合成途径。接下来，我们描述了几种神经回路中内源性阿片肽表达组织的示例，以及它们似乎如何从特定的神经区室释放，而这些神经区室在不同的脑区中有所不同。我们讨论了关于驱动内源性阿片肽释放所需的神经活动强度的现有知识，有关肽从释放部位扩散多远的线索，以及它们在释放后的细胞外寿命。最后，作为一个转化的例子，我们讨论了纳曲酮（NTX）的作用机制，NTX 临床上用于治疗酒精使用障碍。NTX 是一种合成的吗啡类似物，它在 20 世纪 60 年代开发并于 20 世纪 80 年代获得 FDA 批准，非特异性拮抗大多数内源性阿片肽的作用。我们综述了最近的研究，这些研究阐明了 NTX 预防的确切内源性作用。总之，这里描述的工作强调了复杂的阿片系统作为治疗靶点所带来的挑战和机遇。
Zotero 插件
