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 (μ, δ, or κ), 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.

中文翻译：

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阿片类肽研究的五个十年：当前知识和未解决的问题。

在 1970 年代中期，一场旨在识别激活与阿片类药物相同受体的内源性物质的激烈竞争导致了第一个内源性阿片肽的识别。从那时起，已经发现了超过 20 种具有阿片受体活性的肽，所有这些肽都是由三种前体（脑啡肽原、强啡肽原和阿片黑素皮质素原）通过激素原转化酶和羧肽酶 E 的顺序蛋白水解加工产生的。 这些肽中的每一种都与所有这三种结合阿片受体类型（μ、δ 或 κ），尽管具有不同的亲和力。源自脑啡肽原和强啡肽原的肽广泛分布于大脑中，编码所有三种前体的 mRNA 在一些外周组织中高度表达。已使用各种方法来探索阿片肽在特定行为和大脑回路中的功能。这些方法包括直接离体（即切除的组织）或体内（在动物体内）施用肽，使用阿片受体拮抗剂来推断内源性肽活性，以及​​基因敲除阿片肽前体。总的来说，这些研究增加了我们目前对内源性阿片类药物功能的理解，特别是当使用不同方法发现类似结果时。我们简要回顾了阿片肽的鉴定历史，突出了主要发现，解决了一些被广泛接受但不受最近数据支持的神话，并讨论了未解决的问题和未来的研究方向。意义声明：阿片类药物和合成药物激活阿片受体会导致中枢和外周生物效应，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和重叠的作用，研究的一个重要方向是描绘单个肽的作用。