Gomes I, Jordan B A, Gupta A, Trapaidze N, Nagy V, Devi L A
Departments of Pharmacology and Anesthesiology, New York University School of Medicine, New York, New York 10016, USA.
J Neurosci. 2000 Nov 15;20(22):RC110. doi: 10.1523/JNEUROSCI.20-22-j0007.2000.
Opiate analgesics are widely used in the treatment of severe pain. Because of their importance in therapy, different strategies have been considered for making opiates more effective while curbing their liability to be abused. Although most opiates exert their analgesic effects primarily via mu opioid receptors, a number of studies have shown that delta receptor-selective drugs can enhance their potency. The molecular basis for these findings has not been elucidated previously. In the present study, we examined whether heterodimerization of mu and delta receptors could account for the cross-modulation previously observed between these two receptors. We find that co-expression of mu and delta receptors in heterologous cells followed by selective immunoprecipitation results in the isolation of mu-delta heterodimers. Treatment of these cells with extremely low doses of certain delta-selective ligands results in a significant increase in the binding of a mu receptor agonist. Similarly, treatment with mu-selective ligands results in a significant increase in the binding of a delta receptor agonist. This robust increase is also seen in SKNSH cells that endogenously express both mu and delta receptors. Furthermore, we find that a delta receptor antagonist enhances both the potency and efficacy of the mu receptor signaling; likewise a mu antagonist enhances the potency and efficacy of the delta receptor signaling. A combination of agonists (mu and delta receptor selective) also synergistically binds and potentiates signaling by activating the mu-delta heterodimer. Taken together, these studies show that heterodimers exhibit distinct ligand binding and signaling characteristics. These findings have important clinical ramifications and may provide new foundations for more effective therapies.
阿片类镇痛药广泛用于治疗重度疼痛。由于其在治疗中的重要性，人们考虑了不同策略以提高阿片类药物的疗效，同时抑制其被滥用的可能性。尽管大多数阿片类药物主要通过μ阿片受体发挥镇痛作用，但多项研究表明，δ受体选择性药物可增强其效力。这些发现的分子基础此前尚未阐明。在本研究中，我们探究了μ和δ受体的异二聚化是否可以解释此前在这两种受体之间观察到的交叉调节。我们发现，在异源细胞中共表达μ和δ受体，随后进行选择性免疫沉淀，可分离出μ-δ异二聚体。用极低剂量的某些δ选择性配体处理这些细胞，会导致μ受体激动剂的结合显著增加。同样，用μ选择性配体处理会导致δ受体激动剂的结合显著增加。在内源性表达μ和δ受体的SKNSH细胞中也观察到这种显著增加。此外，我们发现δ受体拮抗剂可增强μ受体信号传导的效力和功效；同样，μ拮抗剂可增强δ受体信号传导的效力和功效。激动剂组合（μ和δ受体选择性）也通过激活μ-δ异二聚体协同结合并增强信号传导。综上所述，这些研究表明异二聚体表现出独特的配体结合和信号传导特征。这些发现具有重要的临床意义，可能为更有效的治疗提供新的基础。
