Fujita Wakako
Department of Medical Pharmacology, Nagasaki University Graduate School of Biomedical Sciences.
Nihon Yakurigaku Zasshi. 2021;156(3):134-138. doi: 10.1254/fpj.20103.
Many studies suggest opioid receptor (OPr) dimerization modulates the pharmacological properties of opiates. Specifically, heteromerization between OPr types has been reported to lead to changes in intracellular signaling. Thus, ligands targeting heteromers are expected to be novel therapeutic targets with reduced side effects. The heteromers of mu (MOPr) and delta (DOPr) are detected in brain regions involved in pain processing. The bivalent ligand or small molecule were identified as a MOPr-DOPr targeting ligand. These ligands exhibit antinociceptive properties similar to that of morphine with lesser antinociceptive tolerance as compared to morphine. Studies exploring the in vivo regulation of MOPr-DOPr heteromers, showed chronic morphine administration leads to an upregulation of these heteromers in select brain regions. Exploration of mechanisms underlying this phenomenon led us to the G protein-coupled receptor chaperone, RTP4, that is induced by chronic morphine and facilitates the heteromerization of MOPr and DOPr. In this review, I will introduce the simulated structure or property of MOPr-DOPr heteromer, its targeting ligands, and its intracellular regulatory mechanism that include a key molecule like RTP4 that could serve as a scaffold for the development of novel therapeutic drugs with reduced adverse effects, and hence may take place of the conventional clinical opioids.
许多研究表明阿片受体（OPr）二聚化可调节阿片类药物的药理特性。具体而言，据报道不同类型的OPr之间的异源二聚化会导致细胞内信号传导的变化。因此，靶向异源二聚体的配体有望成为副作用更小的新型治疗靶点。在参与疼痛处理的脑区中检测到了μ（MOPr）和δ（DOPr）阿片受体的异源二聚体。已鉴定出二价配体或小分子为靶向MOPr-DOPr的配体。这些配体表现出与吗啡相似的镇痛特性，但与吗啡相比，镇痛耐受性较小。探索MOPr-DOPr异源二聚体体内调节的研究表明，长期给予吗啡会导致这些异源二聚体在特定脑区上调。对这一现象潜在机制的探索使我们发现了G蛋白偶联受体伴侣RTP4，它由慢性吗啡诱导，并促进MOPr和DOPr的异源二聚化。在这篇综述中，我将介绍MOPr-DOPr异源二聚体的模拟结构或特性、其靶向配体及其细胞内调节机制，其中包括关键分子RTP4，它可为开发副作用更小的新型治疗药物提供框架，因此可能会取代传统的临床阿片类药物。
