Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (L.D.F.); Department of Neurology, UCSF Weill Institute for Neurosciences, San Francisco, California (E.B.M.); and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.)
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York (L.D.F.); Department of Neurology, UCSF Weill Institute for Neurosciences, San Francisco, California (E.B.M.); and Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York (I.G., L.A.D.).
Mol Pharmacol. 2020 Aug;98(2):96-108. doi: 10.1124/mol.120.119388. Epub 2020 Jun 2.
In the mid-1970s, an intense race to identify endogenous substances that activated the same receptors as opiates resulted in the identification of the first endogenous opioid peptides. Since then, >20 peptides with opioid receptor activity have been discovered, all of which are generated from three precursors, proenkephalin, prodynorphin, and proopiomelanocortin, by sequential proteolytic processing by prohormone convertases and carboxypeptidase E. Each of these peptides binds to all three of the opioid receptor types (, , or ), albeit with differing affinities. Peptides derived from proenkephalin and prodynorphin are broadly distributed in the brain, and mRNA encoding all three precursors are highly expressed in some peripheral tissues. Various approaches have been used to explore the functions of the opioid peptides in specific behaviors and brain circuits. These methods include directly administering the peptides ex vivo (i.e., to excised tissue) or in vivo (in animals), using antagonists of opioid receptors to infer endogenous peptide activity, and genetic knockout of opioid peptide precursors. Collectively, these studies add to our current understanding of the function of endogenous opioids, especially when similar results are found using different approaches. We briefly review the history of identification of opioid peptides, highlight the major findings, address several myths that are widely accepted but not supported by recent data, and discuss unanswered questions and future directions for research. SIGNIFICANCE STATEMENT: Activation of the opioid receptors by opiates and synthetic drugs leads to central and peripheral biological effects, including analgesia and respiratory depression, but these may not be the primary functions of the endogenous opioid peptides. Instead, the opioid peptides play complex and overlapping roles in a variety of systems, including reward pathways, and an important direction for research is the delineation of the role of individual peptides.
在上世纪 70 年代中期，一场激烈的竞赛旨在鉴定出与阿片类药物激活相同受体的内源性物质，从而鉴定出第一批内源性阿片肽。从那时起，已经发现了超过 20 种具有阿片受体活性的肽，它们都由三种前体——脑啡肽原、强啡肽原和前阿黑皮素原通过激素原转化酶和羧肽酶 E 的顺序蛋白水解加工产生。这些肽中的每一种都与三种阿片受体类型（μ、δ 或 κ）结合，尽管亲和力不同。来源于脑啡肽原和强啡肽原的肽广泛分布于大脑中，编码这三种前体的 mRNA 在一些外周组织中高度表达。已经采用了各种方法来探索阿片肽在特定行为和大脑回路中的功能。这些方法包括体外（即在离体组织中）或体内（在动物中）直接给予肽、使用阿片受体拮抗剂推断内源性肽的活性，以及基因敲除阿片肽前体。这些研究共同增加了我们对内源性阿片类物质功能的理解，尤其是当使用不同方法得到相似结果时。我们简要回顾了阿片肽的鉴定历史，强调了主要发现，讨论了几个被广泛接受但没有得到最新数据支持的误区，并探讨了未解决的问题和未来的研究方向。意义陈述：阿片类药物和合成药物激活阿片受体导致中枢和外周生物学效应，包括镇痛和呼吸抑制，但这些可能不是内源性阿片肽的主要功能。相反，阿片肽在包括奖励途径在内的各种系统中发挥着复杂且重叠的作用，研究的一个重要方向是阐明个体肽的作用。
