Untangling the complexity of opioid receptor function.
Untangling the complexity of opioid receptor function.
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DOI：
10.1038/s41386-018-0225-3
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
Volkow ND
中科院分区：
文献类型：
--
作者：
Valentino RJ;Volkow ND
MU阿片受体激动剂是最有效的止痛药之一，但也是最容易上瘾的药物之一。目前的阿片类药物危机促使人们寻求开发没有不良影响的阿片类止痛药。自20世纪70年代S发现这些药物以来，我们对这些药物针对的内源性阿片系统的理解取得了重大进展。然而，许多问题仍然存在，非成瘾性阿片类镇痛剂的开发尚未实现。然而，获得新的分子、遗传和计算工具已经开始阐明阿片受体的结构动力学，将它们与细胞内信号级联联系起来的支架，它们的细胞运输，以及各种阿片类药物修改它们的不同方式。这篇小型综述强调了使用这些工具进行研究时出现的一些化学和药理学发现和新的观点。它们揭示了阿片受体功能的多层次复杂性，包括阿片受体诱导的细胞信号的时空特异性、配基导向的偏向信号、配基相互作用的变构调节、不同阿片受体的异构化以及具有不同配基特异性的片断变体的存在。通过解开这些层面，对阿片受体化学和药理学的基础研究正在引导人们破解困扰该领域的耐受和身体依赖的谜团，并为开发更有效、更安全的阿片类药物提供平台。
Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970’s, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.
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