BACKGROUND AND OBJECTIVE The recent alarming reports related to "opioid crisis" necessitate the development of safer and effective analgesics without unwanted side effects. Thus, there needs to be an alternative target or strategy for the development of drugs for the treatment of opioid use/abuse. As one of the novel targets, in these two decades, ligands targeting opioid receptor "heteromerization" including mu-opioid receptor (MOPr)-delta opioid receptor (DOPr) heteromer have been proposed and the pharmacological advancement of reduced side effects has been broadly accepted and well recognized. In this review, some of the ligands targeting both MOPr and DOPr or MOPr-DOPr heteromers are introduced especially focusing on their pharmacological effects in vivo. CONCLUSION It has been found that most of those ligands possess potent antinociceptive activity (as much as or higher than that of morphine) with reduced side effects such as tolerance. In addition, some of them are also able to reduce or prevent physiological withdrawal symptoms observed under chronic opioid use. Importantly, there are an increasing number of evidence that show changes in heteromer expression in various pathological animal models and these strongly argue for targeting heteromers for the development of the next generation of pain medication in the near future.

中文翻译：

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针对理想疗法-MOPr/DOPr 或MOPr-DOPr 异聚体靶向配体。

背景和目的 最近与“阿片类药物危机”相关的令人震惊的报告要求开发更安全、有效且无副作用的镇痛药。因此，需要有一个替代目标或策略来开发治疗阿片类药物使用/滥用的药物。作为新靶点之一，在这二十年中，已经提出了靶向阿片受体“异聚化”的配体，包括μ-阿片受体（MOPr）-δ阿片受体（DOPr）异聚体，减少副作用的药理学进展已被广泛接受并广为人知。在这篇综述中，介绍了一些针对 MOPr 和 DOPr 或 MOPr-DOPr 异聚体的配体，特别关注它们的体内药理作用。结论 已经发现，这些配体中的大多数都具有有效的镇痛活性（与吗啡一样多或更高），并且副作用如耐受性降低。此外，其中一些还能够减少或预防在长期使用阿片类药物时观察到的生理戒断症状。重要的是，越来越多的证据表明在各种病理动物模型中异聚体表达发生了变化，这些证据强烈支持在不久的将来开发下一代止痛药的靶向异聚体。