Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain.
Morphine and gp120 toxic interactions in striatal neurons are dependent on HIV-1 strain.
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DOI：
10.1007/s11481-011-9326-z
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发表时间：
2012-12
影响因子：
6.2
通讯作者：
Hauser, Kurt F.
中科院分区：
文献类型：
--
作者：
Podhaizer, Elizabeth M.;Zou, Shiping;Fitting, Sylvia;Samano, Kimberly L.;El-Hage, Nazira;Knapp, Pamela E.;Hauser, Kurt F.
关键词：
使用严格控制的细胞培养范例来评估HIV-1 gp 120 ±吗啡在纹状体神经元中介导阿片样物质-HIV相互作用毒性中的作用。计算机化的延时显微镜追踪在阿片和gp 120暴露期间与来自小鼠纹状体的混合胶质细胞共培养的单个神经元的命运。神经元和星形胶质细胞亚群显示μ-阿片受体、CXCR 4和CCR 5免疫反应性。虽然单独的gp 120是或倾向于神经毒性的，无论是否给予X4-嗜性gp 120 IIIB、R5-嗜性gp 120 ADA或双嗜性gp 120 MN，与吗啡的相互作用毒性根据HIV-1毒株而不同。例如，吗啡仅短暂加剧gp 120 IIIB诱导的神经元死亡;然而，与gp 120 MN联合使用时，与纳洛酮预防的单独gp 120 MN相比，吗啡导致神经元死亡率持续增加。另外，gp 120 ADA显著增加神经元死亡率，这不受吗啡的影响。吗啡和gp 120 IIIB之间的短暂神经毒性相互作用在没有神经胶质细胞的情况下被废除，这表明神经胶质细胞对慢性阿片类药物滥用和neuroAIDS的相互作用病理学有显着贡献。为了评估混合神经胶质细胞如何可能导致神经毒性，研究了吗啡和/或gp 120对活性氧（ROS）产生和谷氨酸缓冲的影响。所有的gp 120变体，以及在较小程度上吗啡，增加ROS和/或减少谷氨酸缓冲，但一起没有显示出与吗啡的任何相互作用。我们的研究结果表明，HIV-1株特异性gp 120的差异是塑造与阿片类药物的神经毒性相互作用的时间和模式的关键决定因素。
A rigorously controlled, cell culture paradigm was used to assess the role of HIV-1 gp120 ± morphine in mediating opioid-HIV interactive toxicity in striatal neurons. Computerized time-lapse microscopy tracked the fate of individual neurons co-cultured with mixed-glia from mouse striata during opioid and gp120 exposure. Subpopulations of neurons and astroglia displayed μ-opioid receptor, CXCR4, and CCR5 immunoreactivity. While gp120 alone was or tended to be neurotoxic irrespective of whether X4-tropic gp120IIIB, R5-tropic gp120ADA, or dual-tropic gp120MN was administered, interactive toxicity with morphine differed depending on HIV-1 strain. For example, morphine only transiently exacerbated gp120IIIB-induced neuronal death; however, in combination with gp120MN, morphine caused sustained increases in the rate of neuronal death compared to gp120MN alone that were prevented by naloxone. Alternatively, gp120ADA significantly increased the rate of neuron death, which was unaffected by morphine. The transient neurotoxic interactions between morphine and gp120IIIB were abrogated in the absence of glia suggesting that glia contribute significantly to the interactive pathology with chronic opiate abuse and neuroAIDS. To assess how mixed-glia might contribute to the neurotoxicity, the effects of morphine and/or gp120 on the production of reactive oxygen species (ROS) and on glutamate buffering were examined. All gp120 variants, and to a lesser extent morphine, increased ROS and/or decreased glutamate buffering, but together failed to show any interaction with morphine. Our findings indicate that HIV-1 strain-specific differences in gp120 are critical determinants in shaping both the timing and pattern of neurotoxic interactions with opioid drugs.
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