Wodarski Rachel, Bagdas Deniz, Paris Jason J, Pheby Tim, Toma Wisam, Xu Ruqiang, Damaj M Imad, Knapp Pamela E, Rice Andrew S C, Hauser Kurt F
Pain Research Group, Department of Surgery and Cancer, Imperial College, Chelsea and Westminster Hospital Campus, London, United Kingdom.
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Pain Rep. 2018 May 14;3(3):e654. doi: 10.1097/PR9.0000000000000654. eCollection 2018 May.
HIV infection is associated with chronic pain states, including sensory neuropathy, which affects greater than 40% of patients.
To determine the impact of HIV-Tat induction on nociceptive behaviour in female mice conditionally expressing HIV Tat protein through a doxycycline (DOX)-driven glial fibrillary acidic protein promoter, intraepidermal nerve fibre density and immune cell activation in the dorsal root ganglion (DRG) and spinal cord were assessed by immunohistochemistry. Mice were assessed for mechanical and thermal sensitivity for 9 weeks using von-Frey and Hargreaves tests.
Intraepidermal nerve fibre density was significantly reduced after 6 weeks of Tat induction, similar to sensory neuropathy seen in clinical HIV infection. Tat induction through DOX caused a significant reduction in paw withdrawal thresholds in a time-dependent manner starting the 4th week after Tat induction. No changes in paw withdrawal latencies were seen in Tat(-) control mice lacking the transgene. Although reductions in paw withdrawal thresholds increased throughout the study, no significant change in spontaneous motor activity was observed. Spinal cord (cervical and lumbar), DRG, and hind paw skin were collected at 8 days and 6 weeks after Tat induction. HIV-Tat mRNA expression was significantly increased in lumbar DRG and skin samples 8 days after DOX treatment. Tat induced a significant increase in the number of Iba-1 positive cells at 6 weeks, but not after 8 days, of exposure. No differences in glial fibrillary acidic protein immunoreactivity were observed.
These results suggest that Tat protein contributes to painful HIV-related sensory neuropathy during the initial stages of the pathogenesis.
HIV感染与慢性疼痛状态有关，包括感觉神经病变，超过40%的患者受其影响。
为了确定HIV-Tat诱导对有条件通过强力霉素（DOX）驱动的胶质纤维酸性蛋白启动子表达HIV Tat蛋白的雌性小鼠伤害感受行为的影响，通过免疫组织化学评估表皮内神经纤维密度以及背根神经节（DRG）和脊髓中的免疫细胞激活情况。使用von-Frey和哈格里夫斯试验对小鼠进行9周的机械和热敏感性评估。
Tat诱导6周后，表皮内神经纤维密度显著降低，类似于临床HIV感染中所见的感觉神经病变。通过DOX诱导Tat以时间依赖性方式导致爪退缩阈值从Tat诱导后第4周开始显著降低。在缺乏转基因的Tat(-)对照小鼠中未观察到爪退缩潜伏期的变化。尽管在整个研究过程中爪退缩阈值的降低有所增加，但未观察到自发运动活动的显著变化。在Tat诱导后8天和6周收集脊髓（颈段和腰段）、DRG和后爪皮肤。DOX处理8天后，腰段DRG和皮肤样本中HIV-Tat mRNA表达显著增加。Tat暴露6周时诱导Iba-1阳性细胞数量显著增加，但8天后未增加。未观察到胶质纤维酸性蛋白免疫反应性的差异。
这些结果表明，Tat蛋白在发病机制的初始阶段促成了与HIV相关的疼痛性感觉神经病变。
