1月13日,美国《神经元》Neuron杂志发表了中科院上海生科院神经所张旭研究员和生化与细胞所鲍岚研究员领导的科研团队的研究成果— “Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated co-degradation”。这一成果是由神经所研究生何绍球、管吉松和生化细胞研究所研究生张振宁等共同完成。
吗啡等阿片类药物是目前最有效的镇痛药,但易造成耐受和依赖等副作用。脊髓中阿片肽及其受体组成痛觉抑制性调制系统,其中μ阿片受体介导吗啡等镇痛药的作用,δ阿片受体介导内源性脑啡肽的作用。以往研究提示δ阿片受体可以与μ阿片受体形成异源多聚体,同时负向调控μ阿片受体介导的镇痛功能。然而,人们对其中的机制还了解得很少。
作者通过一系列的实验发现,阻止μ阿片受体进入δ阿片受体介导的受体降解途径可以增强μ阿片受体介导的镇痛效力。在δ阿片受体特异性的激动剂刺激下,位于细胞膜上的δ阿片受体和μ阿片受体共同被内吞进入细胞内,并主要进入溶酶体进行降解。他们还发现μ阿片受体的第一次跨膜段介导了其与δ阿片受体的结合,因此设计了将帮助大分子穿膜的TAT肽段连接于μ阿片受体第一次跨膜段C端的干扰蛋白,用于解除脊髓痛觉传导通路中两类阿片受体间的相互作用。动物实验表明,注射该干扰蛋白可以阻碍脊髓内的δ阿片受体和μ阿片受体相互作用,不但提高了吗啡的镇痛效果,而且降低吗啡的耐受作用。这些结果提示,激活δ阿片受体可以造成两类阿片受体的共同内吞和降解,该机制对μ阿片受体的脱敏起着很重要的调节作用。该研究结果为提高阿片类镇痛剂的镇痛效果提供了一种新策略。
该工作得到了中国科学院、科技部973项目、国家自然科学基金等项目的资助。(生物谷Bioon.com)
生物谷推荐原文出处:
Neuron. 2011 Jan 13;69(1):120-31.
Facilitation of μ-Opioid Receptor Activity by Preventing δ-Opioid Receptor-Mediated Codegradation.
He SQ, Zhang ZN, Guan JS, Liu HR, Zhao B, Wang HB, Li Q, Yang H, Luo J, Li ZY, Wang Q, Lu YJ, Bao L, Zhang X.
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China.
Abstract
δ-opioid receptors (DORs) form heteromers with μ-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 (MOR(TM1)), which interacted with DORs and disrupted the MOR/DOR interaction. Furthermore, the systemically applied fusion protein consisting of MOR(TM1) 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.