Liao Dezhi, Grigoriants Olga O, Wang Wei, Wiens Katie, Loh Horace H, Law Ping-Yee
Department of Neuroscience and Basic Research Center on Molecular and Cell Biology of Drug Addiction, The University of Minnesota, 321 Church St SE, Minneapolis, MN 55455, USA.
Mol Cell Neurosci. 2007 Jul;35(3):456-69. doi: 10.1016/j.mcn.2007.04.007. Epub 2007 May 4.
This study has examined the relationship between the effects of opioids on the internalization of mu opioid receptors (MORs) and the morphology of dendritic spines. Several opioids (morphine, etorphine, DAMGO or methadone) were applied to cultured hippocampal neurons. Live imaging and biochemical techniques were used to examine the dynamic changes in MOR internalization and spine morphology. This study reveals that MOR internalization can regulate opioid-induced morphological changes in dendritic spines: (1) Chronic treatment with morphine, which induced minimal receptor internalization, caused collapse of dendritic spines. In contrast, "internalizing" opioids such as DAMGO and etorphine induced the emergence of new spines. It reveals that opioid-induced changes in spines vary greatly depending on how the applied opioid agonist affects MOR internalization. (2) The blockade of receptor internalization by dominant negative mutant of dynamin, K44E, reversed the effects of DAMGO and etorphine. It indicates that receptor internalization is necessary for the distinct effects of DAMGO and etorphine on spines. (3) In neurons that were cultured from MOR knock-out mice and had been co-transfected with DsRed and MOR-GFP, morphine caused collapse of spines whereas DAMGO induced emergence of new spines, indicating that opioids can alter the structure of spines via postsynaptic MORs. (4) Methadone at a low concentration induced minimal internalization and had effects that were similar to morphine. At a high concentration, methadone induced robust internalization and had effects that are opposite to morphine. The concentration-dependent opioid-induced changes in dendritic spines might also contribute to the variation in the effects of individual opioids.
本研究考察了阿片类药物对μ阿片受体（MORs）内化作用的影响与树突棘形态之间的关系。将几种阿片类药物（吗啡、埃托啡、DAMGO或美沙酮）应用于培养的海马神经元。采用实时成像和生化技术来检测MOR内化和树突棘形态的动态变化。本研究表明，MOR内化可调节阿片类药物诱导的树突棘形态变化：（1）长期用吗啡处理，其诱导的受体内化极少，导致树突棘塌陷。相反，“内化型”阿片类药物如DAMGO和埃托啡则诱导新的树突棘出现。这表明阿片类药物诱导的树突棘变化因所应用的阿片类激动剂对MOR内化的影响方式不同而有很大差异。（2）发动蛋白的显性负突变体K44E对受体内化的阻断作用，逆转了DAMGO和埃托啡的作用。这表明受体内化对于DAMGO和埃托啡对树突棘的独特作用是必要的。（3）在从MOR基因敲除小鼠培养并共转染了DsRed和MOR-GFP的神经元中，吗啡导致树突棘塌陷，而DAMGO则诱导新的树突棘出现，表明阿片类药物可通过突触后MORs改变树突棘的结构。（4）低浓度美沙酮诱导的内化极少，其作用与吗啡相似。高浓度时，美沙酮诱导强烈的内化，其作用与吗啡相反。阿片类药物诱导的树突棘浓度依赖性变化也可能导致个体阿片类药物作用的差异。
