Evidence from several novel opioid agonists and knockout animals suggests that improved opioid therapeutic window, notably for analgesia versus respiratory depression, is a result of ligand bias downstream of activation of the µ-opioid receptor (MOR) toward G protein signaling and away from other pathways, such as arrestin recruitment. Here, we argue that published claims of opioid bias based on application of the operational model of agonism are frequently confounded by failure to consider the assumptions of the model. These include failure to account for intrinsic efficacy and ceiling effects in different pathways, distortions introduced by analysis of amplified (G protein) versus linear (arrestin) signaling mechanisms, and nonequilibrium effects in a dynamic signaling cascade. We show on both theoretical and experimental grounds that reduced intrinsic efficacy that is unbiased across different downstream pathways, when analyzed without due considerations, does produce apparent but erroneous MOR ligand bias toward G protein signaling, and the weaker the G protein partial agonism is the greater the apparent bias. Experimentally, such apparently G protein–biased opioids have been shown to exhibit low intrinsic efficacy for G protein signaling when ceiling effects are properly accounted for. Nevertheless, such agonists do display an improved therapeutic window for analgesia versus respiratory depression. Reduced intrinsic efficacy for G proteins rather than any supposed G protein bias provides a more plausible, sufficient explanation for the improved safety. Moreover, genetic models of G protein–biased opioid receptors and replication of previous knockout experiments suggest that reduced or abolished arrestin recruitment does not improve therapeutic window for MOR-induced analgesia versus respiratory depression.

中文翻译：

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阿片类药物配体的内在功效及其对表观偏见，操作分析和治疗窗口的重要性。

几种新颖的阿片类激动剂和基因敲除动物的证据表明，阿片类药物治疗窗口的改善（尤其是对镇痛和呼吸抑制的作用）是μ激活下游配体偏倚的结果。-类鸦片受体（MOR）朝向G蛋白信号转导，并远离其他途径，例如抑制蛋白募集。在这里，我们认为基于激动性操作模型的应用发表的阿片类药物偏倚的主张常常由于未能考虑模型的假设而混淆。这些包括无法解释不同途径中的内在功效和上限效应，通过分析扩增（G蛋白）与线性（arrestin）信号传导机制而引入的失真以及动态信号传导级联中的非平衡效应。我们在理论和实验基础上均显示，在不作任何适当考虑的情况下进行分析时，降低的内在功效在不同的下游途径之间没有偏倚，的确会产生明显但错误的MOR配体偏向G蛋白信号传导，G蛋白部分激动作用越弱，表观偏差越大。从实验上看，当适当考虑上限效应时，这种明显偏向G蛋白的阿片类药物显示出对G蛋白信号传导的低内在功效。然而，这种激动剂确实显示出改善的镇痛与呼吸抑制相比的治疗窗口。G蛋白的内在功效降低，而不是任何G蛋白偏倚，为提高安全性提供了更合理，充分的解释。此外，G蛋白偏向阿片受体的遗传模型和先前基因敲除实验的复制表明，减少或取消的抑制素募集并不能改善MOR引起的镇痛和呼吸抑制的治疗窗口。当适当考虑上限效应时，这种明显地偏向G蛋白的阿片类药物显示出对G蛋白信号传导的低内在功效。然而，这种激动剂确实显示出改善的镇痛与呼吸抑制相比的治疗窗口。G蛋白的内在功效降低，而不是任何G蛋白偏倚，为提高安全性提供了更合理，充分的解释。此外，G蛋白偏向阿片受体的遗传模型和先前基因敲除实验的复制表明，减少或取消的抑制素募集并不能改善MOR引起的镇痛和呼吸抑制的治疗窗口。当适当考虑上限效应时，这种明显地偏向G蛋白的阿片类药物显示出对G蛋白信号传导的低内在功效。然而，这种激动剂确实显示出改善的镇痛与呼吸抑制相比的治疗窗口。G蛋白的内在功效降低，而不是任何G蛋白偏倚，为提高安全性提供了更合理，充分的解释。此外，G蛋白偏向阿片受体的遗传模型和先前基因敲除实验的复制表明，减少或取消的抑制素募集并不能改善MOR引起的镇痛和呼吸抑制的治疗窗口。然而，这种激动剂确实显示出改善的镇痛与呼吸抑制相比的治疗窗口。G蛋白的内在功效降低，而不是任何G蛋白偏倚，为提高安全性提供了更合理，充分的解释。此外，G蛋白偏向阿片受体的遗传模型和先前基因敲除实验的复制表明，减少或取消的抑制素募集并不能改善MOR引起的镇痛和呼吸抑制的治疗窗口。然而，这种激动剂确实显示出改善的镇痛与呼吸抑制相比的治疗窗口。G蛋白的内在功效降低，而不是任何G蛋白偏倚，为提高安全性提供了更合理，充分的解释。此外，G蛋白偏向阿片受体的遗传模型和先前基因敲除实验的复制表明，减少或取消的抑制素募集并不能改善MOR引起的镇痛和呼吸抑制的治疗窗口。