Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation
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DOI：
10.1016/j.neuron.2010.12.001
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发表时间：
2011-01-13
期刊：
影响因子：
16.2
通讯作者：
Zhang, Xu
中科院分区：
文献类型：
--
作者：
He, Shao-Qiu;Zhang, Zhen-Ning;Zhang, Xu
delta-阿片受体（DORs）与mu-阿片受体（MORs）形成异构体，负向调节MORs介导的脊髓镇痛。然而，潜在的机制在很大程度上仍不清楚。目前的研究表明，可以通过阻止MORs介导的编码降解来增强MORs的活性。用dor特异性激动剂治疗可导致dor和MORs的内吞作用。这些受体进一步处理泛素化和溶酶体降解，导致表面MORs减少。通过含有MOR第一跨膜结构域的干扰肽（MORTm1）处理，这种效应减弱，该肽与DORs相互作用并破坏MOR/DOR相互作用。此外，系统应用由MORTM1和C端TAT组成的融合蛋白可以破坏小鼠脊髓中MOR/DOR的相互作用，增强吗啡镇痛，降低吗啡的抗痛觉性耐受性。因此，MORs与DORs在细胞膜上的分离是改善阿片类镇痛治疗的潜在策略。
delta-opioid receptors (DORs) form heteromers with mu-opioid receptors (MORs) and negatively regulate MOR-mediated spinal analgesia. However, the underlying mechanism remains largely unclear. The present study shows that the activity of MORs can be enhanced by preventing MORs from DOR-mediated codegradation. Treatment with DOR-specific agonists led to endocytosis of both DORs and MORs. These receptors were further processed for ubiquitination and lysosomal degradation, resulting in a reduction of surface MORs. Such effects were attenuated by treatment with an interfering peptide containing the first transmembrane domain of MOR (MORTm1), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MORTM1 and TAT at the C terminus could disrupt the MOR/DOR interaction in the mouse spinal cord, enhance the morphine analgesia, and reduce the antinociceptive tolerance to morphine. Thus, dissociation of MORs from DORs in the cell membrane is a potential strategy to improve opioid analgesic therapies.