Iida T, Yi H, Liu S, Ikegami D, Zheng W, Liu Q, Takahashi K, Kashiwagi Y, Goins W F, Glorioso J C, Hao S
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Microbiology and Molecular Genetics, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.
Gene Ther. 2017 May;24(5):314-324. doi: 10.1038/gt.2017.22. Epub 2017 Apr 3.
Morphine appears to be the most active metabolite of heroin; therefore, the effects of morphine are important in understanding the ramifications of heroin abuse. Opioid physical dependence (withdrawal response) may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. However, the exact mechanisms of morphine withdrawal (MW) are not clear yet, and its treatment remains elusive. Periaqueductal gray (PAG) is one of the important sites in the pathogenesis of MW. Here, we used recombinant herpes simplex virus (HSV) vectors that encode the sod2 gene expressing manganese superoxide dismutase (MnSOD) to evaluate its therapeutic potential in MW. Microinjection of HSV vectors expressing MnSOD into the PAG reduced the MW syndrome. MnSOD vectors suppressed the upregulated mitochondrial superoxide, and endoplasmic reticulum stress markers (glucose-related protein 78 (GRP78) and activating transcription factor 6 alpha (ATF6α)) in the PAG induced by MW. Immunostaining showed that mitochondrial superoxide, GRP78 and ATF6α were colocalized with neuronal nuclei (a neuronal-specific marker), suggesting that they are located in the neurons in the PAG. These results suggest that overexpression of MnSOD by HSV vectors may relieve opioid dependence. This study may provide a novel therapeutic approach to morphine physical withdrawal response.
吗啡似乎是海洛因最具活性的代谢产物；因此，吗啡的作用对于理解海洛因滥用的后果至关重要。阿片类物质身体依赖（戒断反应）可能对奖赏动机产生非常持久的影响，包括线索诱导的觅药行为的潜伏期。然而，吗啡戒断（MW）的确切机制尚不清楚，其治疗方法仍然难以捉摸。导水管周围灰质（PAG）是MW发病机制中的重要部位之一。在此，我们使用编码表达锰超氧化物歧化酶（MnSOD）的sod2基因的重组单纯疱疹病毒（HSV）载体来评估其在MW中的治疗潜力。将表达MnSOD的HSV载体微量注射到PAG中可减轻MW综合征。MnSOD载体抑制了MW诱导的PAG中上调的线粒体超氧化物以及内质网应激标志物（葡萄糖调节蛋白78（GRP78）和活化转录因子6α（ATF6α））。免疫染色显示线粒体超氧化物、GRP78和ATF6α与神经元细胞核（一种神经元特异性标志物）共定位，表明它们位于PAG中的神经元内。这些结果表明，HSV载体介导的MnSOD过表达可能减轻阿片类物质依赖。本研究可能为吗啡身体戒断反应提供一种新的治疗方法。
