Morphine Acutely Regulates Opioid Receptor Trafficking Selectively in Dendrites of Nucleus Accumbens Neurons
Morphine Acutely Regulates Opioid Receptor Trafficking Selectively in Dendrites of Nucleus Accumbens Neurons
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DOI：
10.1523/jneurosci.23-10-04324.2003
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发表时间：
2003-05
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影响因子：
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通讯作者：
H. Haberstock-Debić;Marc N. Wein;M. Barrot;E. Colago;Z. Rahman;R. Neve;V. Pickel;E. Nestler;M. von Zastrow;A. Svingos
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作者：
H. Haberstock-Debić;Marc N. Wein;M. Barrot;E. Colago;Z. Rahman;R. Neve;V. Pickel;E. Nestler;M. von Zastrow;A. Svingos
在转染细胞模型中，吗啡对μ-阿片受体（MORs）内化的刺激程度低于阿片肽和其他镇痛药物（如美沙酮），以前的研究报道吗啡在急性或慢性给药后都不会在神经组织中产生可检测到的MORs重新分布。然而，吗啡产生了深刻的生理效应，这就提出了受体运输是否在吗啡的体内作用中起作用的问题。我们研究了阿片药物对伏隔核重组和天然阿片受体的影响，这些受体在阿片药物的行为效应中起着重要的介导作用。通过病毒基因转移和荧光显微镜成像，吗啡和美沙酮对表位标记的MORs在细胞体中内化的影响不同。在培养的细胞中，细胞质尾部的突变导致吗啡诱导的内化，对伏隔核细胞体中的受体运输有类似的影响。令人惊讶的是，与吗啡在细胞体中无法检测到的MOR分布相反，急性吗啡给药在同一神经元的突起中产生了MOR分布的明显变化。免疫电镜观察到急性给药吗啡对内源性MORs的影响相似；急性给药吗啡增加了与树突内膜结构相关的MORs的密度。这些结果提供了吗啡调节MORs在神经元过程中的分布的第一个证据，表明“区室选择性”膜运输代表了一种以前未预料到的阿片受体调节类型，有助于阿片药物对中枢神经系统神经元生理相关群体的体内影响。
Morphine stimulates the internalization of μ-opioid receptors (MORs) in transfected cell models to a lesser degree than opioid peptides and other analgesic drugs, such as methadone, and previous studies have reported that morphine does not produce a detectable redistribution of MORs in neural tissue after either acute or chronic administration. Nevertheless, morphine produces profound physiological effects, raising the question of whether receptor trafficking plays any role in the in vivo actions of morphine. We investigated the effects of opiate drugs on recombinant and native opioid receptors in the nucleus accumbens, which plays an important role in mediating the behavioral effects of opiate drugs. Morphine and methadone differed in their effects on the internalization of epitope-tagged MORs in cell bodies, introduced by viral gene transfer and imaged by fluorescence microscopy. A mutation of the cytoplasmic tail that confers morphine-induced internalization in cultured cells had a similar effect on receptor trafficking in nucleus accumbens cell bodies. Surprisingly, in contrast to its failure to affect MOR distribution detectably in cell bodies, acute morphine administration produced a pronounced change in MOR distribution visualized in the processes of the same neurons. A similar effect of acute morphine administration was observed for endogenously expressed MORs by immunoelectron microscopy; the acute administration of morphine increased the density of MORs associated with internal membrane structures specifically in dendrites. These results provide the first evidence that morphine regulates the distribution of MORs in neuronal processes, suggesting that “compartment-selective” membrane trafficking represents a previously unanticipated type of opioid receptor regulation contributing to the in vivo effects of opiate drugs on a physiologically relevant population of CNS neurons.