Yi H, Iida T, Liu S, Ikegami D, Liu Q, Iida A, Lubarsky D A, Hao S
Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, USA.
Gene Ther. 2017 Apr;24(4):224-233. doi: 10.1038/gt.2017.11. Epub 2017 Mar 16.
Chronic opiates induce the development of physical dependence. Opioid physical dependence characterized by withdrawal symptoms, may have very long-lasting effects on the motivation for reward, including the incubation of cue-induced drug-seeking behavior. Elucidation of the mechanisms involved in physical dependence is crucial to developing more effective treatment strategies for opioid dependence. Chronic morphine induces production of proinflammatory cytokines in regional-specific sites of the brain. Interleukin-4 (IL-4) is a prototypical anti-inflammatory cytokine that globally suppresses proinflammatory cytokines. Here, we used recombinant herpes simplex virus vector S4IL4 that encode mouse il4 gene to evaluate the therapeutic potential of IL-4 in naloxone-precipitation morphine withdrawal (MW). One week after microinjection of the vector S4IL4 into the PAG LacZ or mouse IL-4 immunoreactivity in the vlPAG was visualized. ELISA assay showed that vector S4IL4 into the PAG induced the expression of IL-4. S4IL4 blunted the morphine withdrawal syndrome. S4IL4 suppressed the upregulated TNFα, NR2B and pC/EBPβ in the PAG induced by MW. These results show that inhibition of proinflammatory factor in the PAG suppressed MW. This study may provide a novel therapeutic approach to morphine physical withdrawal symptoms.
慢性阿片类药物会导致身体依赖性的发展。以戒断症状为特征的阿片类身体依赖性，可能会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。阐明身体依赖性所涉及的机制对于开发更有效的阿片类药物依赖治疗策略至关重要。慢性吗啡会在大脑的区域特异性部位诱导促炎细胞因子的产生。白细胞介素-4（IL-4）是一种典型的抗炎细胞因子，可全面抑制促炎细胞因子。在此，我们使用编码小鼠il4基因的重组单纯疱疹病毒载体S4IL4来评估IL-4在纳洛酮诱发的吗啡戒断（MW）中的治疗潜力。将载体S4IL4微量注射到中脑导水管周围灰质（PAG）的LacZ一周后，可见腹侧PAG中的小鼠IL-4免疫反应性。酶联免疫吸附测定（ELISA）显示，将载体S4IL4注入PAG可诱导IL-4的表达。S4IL4减轻了吗啡戒断综合征。S4IL抑制了由MW诱导的PAG中肿瘤坏死因子α（TNFα）、N-甲基-D-天冬氨酸受体2B（NR2B）和磷酸化CCAAT增强子结合蛋白β（pC/EBPβ）的上调。这些结果表明，抑制PAG中的促炎因子可抑制MW。本研究可能为吗啡身体戒断症状提供一种新的治疗方法。
