Opioid analgesics are elective for treating moderate to severe pain but their use is restricted by severe side effects. Signaling bias has been proposed as a viable means for improving this situation. To exploit this opportunity, continuous efforts are devoted to understand how ligand-specific modulations of receptor functions could mediate the different in vivo effects of opioids. Advances in the field have led to the development of biased agonists based on hypotheses that allocated desired and undesired effects to specific signaling pathways. However, the prevalent hypothesis associating β-arrestin to opioid side effects was recently challenged and multiple of the newly developed biased drugs may not display the superior side effects profile that was sought. Moreover, biased agonism at opioid receptors is now known to be time- and cell-dependent, which adds a new layer of complexity for bias estimation. Here, we first review the signaling mechanisms underlying desired and undesired effects of opioids. We then describe biased agonism at opioid receptors and discuss the different perspectives that support the desired and undesired effects of opioids in view of exploiting biased signaling for therapeutic purposes. Finally, we explore how signaling kinetics and cellular background can influence the magnitude and directionality of bias at those receptors.

阿片类镇痛剂可用于治疗中度至重度疼痛，但其使用受到严重副作用的限制。已提出信号偏差作为改善这种情况的可行方法。为了利用这个机会，我们不断努力了解受体功能的配体特异性调节如何在体内介导不同的阿片类药物的影响。该领域的进步导致了基于假设的偏向激动剂的发展，这些假设将期望和不期望的作用分配给特定的信号通路。然而，将 β-arrestin 与阿片类药物副作用相关联的普遍假设最近受到挑战，并且新开​​发的多种偏倚药物可能不会显示出所寻求的优越副作用特征。此外，现在已知阿片受体的偏向激动是时间和细胞依赖性的，这为偏倚估计增加了一层新的复杂性。在这里，我们首先回顾了阿片类药物所需和不良影响的信号机制。然后，我们描述了阿片受体的偏向激动作用，并讨论了支持阿片类药物的期望和不期望效应的不同观点，以利用偏向信号传导用于治疗目的。最后，我们探讨了信号动力学和细胞背景如何影响这些受体偏差的大小和方向性。