Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
Department of Physiology & Biophysics, Virginia Commonwealth University, Richmond, VA 23298.
Proc Natl Acad Sci U S A. 2020 May 26;117(21):11820-11828. doi: 10.1073/pnas.2000712117. Epub 2020 May 11.
Opioids, such as morphine and fentanyl, are widely used for the treatment of severe pain; however, prolonged treatment with these drugs leads to the development of tolerance and can lead to opioid use disorder. The "Opioid Epidemic" has generated a drive for a deeper understanding of the fundamental signaling mechanisms of opioid receptors. It is generally thought that the three types of opioid receptors (μ, δ, κ) are activated by endogenous peptides derived from three different precursors: Proopiomelanocortin, proenkephalin, and prodynorphin. Posttranslational processing of these precursors generates >20 peptides with opioid receptor activity, leading to a long-standing question of the significance of this repertoire of peptides. Here, we address some aspects of this question using a technical tour de force approach to systematically evaluate ligand binding and signaling properties ([S]GTPγS binding and β-arrestin recruitment) of 22 peptides at each of the three opioid receptors. We show that nearly all tested peptides are able to activate the three opioid receptors, and many of them exhibit agonist-directed receptor signaling (functional selectivity). Our data also challenge the dogma that shorter forms of β-endorphin do not exhibit receptor activity; we show that they exhibit robust signaling in cultured cells and in an acute brain slice preparation. Collectively, this information lays the groundwork for improved understanding of the endogenous opioid system that will help in developing more effective treatments for pain and addiction.
阿片类药物，如吗啡和芬太尼，被广泛用于治疗严重疼痛；然而，长期使用这些药物会导致耐受的发展，并可能导致阿片类药物使用障碍。“阿片类药物流行”促使人们深入了解阿片类受体的基本信号转导机制。人们普遍认为，三种类型的阿片受体（μ、δ、κ）被三种不同前体衍生的内源性肽激活：前阿黑皮素原、前脑啡肽和前强啡肽原。这些前体的翻译后加工生成具有阿片受体活性的 >20 种肽，这导致了对这种肽库的重要性的长期存在的问题。在这里，我们使用一种技术壮举方法来解决这个问题的某些方面，系统地评估了 22 种肽在三种阿片受体上的配体结合和信号转导特性（[S]GTPγS 结合和β-arrestin 募集）。我们表明，几乎所有测试的肽都能够激活三种阿片受体，其中许多表现出激动剂导向的受体信号转导（功能选择性）。我们的数据也挑战了β-内啡肽较短形式不表现出受体活性的教条；我们表明它们在培养细胞和急性脑切片制备中表现出强烈的信号转导。总的来说，这些信息为更好地理解内源性阿片系统奠定了基础，这将有助于开发更有效的疼痛和成瘾治疗方法。
