1月13日,，美國《神經(jīng)元》Neuron雜志發(fā)表了中科院上海生科院神經(jīng)所張旭研究員和生化與細(xì)胞所鮑嵐研究員領(lǐng)導(dǎo)的科研團(tuán)隊(duì)的研究成果— “Facilitation of μ-opioid receptor activity by preventing δ-opioid receptor-mediated co-degradation”,。這一成果是由神經(jīng)所研究生何紹球,、管吉松和生化細(xì)胞研究所研究生張振寧等共同完成,。
嗎啡等阿片類藥物是目前最有效的鎮(zhèn)痛藥,，但易造成耐受和依賴等副作用,。脊髓中阿片肽及其受體組成痛覺抑制性調(diào)制系統(tǒng),，其中μ阿片受體介導(dǎo)嗎啡等鎮(zhèn)痛藥的作用,，δ阿片受體介導(dǎo)內(nèi)源性腦啡肽的作用。以往研究提示δ阿片受體可以與μ阿片受體形成異源多聚體,，同時(shí)負(fù)向調(diào)控μ阿片受體介導(dǎo)的鎮(zhèn)痛功能,。然而,，人們對(duì)其中的機(jī)制還了解得很少。
作者通過一系列的實(shí)驗(yàn)發(fā)現(xiàn),，阻止μ阿片受體進(jìn)入δ阿片受體介導(dǎo)的受體降解途徑可以增強(qiáng)μ阿片受體介導(dǎo)的鎮(zhèn)痛效力,。在δ阿片受體特異性的激動(dòng)劑刺激下，位于細(xì)胞膜上的δ阿片受體和μ阿片受體共同被內(nèi)吞進(jìn)入細(xì)胞內(nèi),，并主要進(jìn)入溶酶體進(jìn)行降解,。他們還發(fā)現(xiàn)μ阿片受體的第一次跨膜段介導(dǎo)了其與δ阿片受體的結(jié)合，因此設(shè)計(jì)了將幫助大分子穿膜的TAT肽段連接于μ阿片受體第一次跨膜段C端的干擾蛋白,，用于解除脊髓痛覺傳導(dǎo)通路中兩類阿片受體間的相互作用,。動(dòng)物實(shí)驗(yàn)表明，注射該干擾蛋白可以阻礙脊髓內(nèi)的δ阿片受體和μ阿片受體相互作用,，不但提高了嗎啡的鎮(zhèn)痛效果,，而且降低嗎啡的耐受作用。這些結(jié)果提示,，激活δ阿片受體可以造成兩類阿片受體的共同內(nèi)吞和降解,，該機(jī)制對(duì)μ阿片受體的脫敏起著很重要的調(diào)節(jié)作用。該研究結(jié)果為提高阿片類鎮(zhèn)痛劑的鎮(zhèn)痛效果提供了一種新策略,。
該工作得到了中國科學(xué)院,、科技部973項(xiàng)目、國家自然科學(xué)基金等項(xiàng)目的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
