Department of Anesthesiology, Pain Medicine and Critical Care Medicine, Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine, Chinese Academy of Sciences, Beijing, China; Savaid Medical School, University of Chinese Academy of Science, Beijing, China.
Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburg, PA, USA.
Pain Physician. 2022 Mar;25(2):E271-E283.
It is frequently reported that neuropathic pain is associated with abnormalities in brain function and structure as well as cognitive deficits. However, the contributing mechanisms have remained elusive.
We aimed to investigate the systemic ultrastructural changes of the peripheral nervous system (PNS) and central nervous system (CNS) in rats with trigeminal neuralgia (TN) induced by cobra venom, as well as the effects and mechanisms of electroacupuncture (EA) and pregabalin (PGB) on TN.
This study used an experimental design in rats.
The research took place in the laboratory at the Aviation General Hospital of China Medical University and Beijing Institute of Translational Medicine.
Male Sprague-Dawley rats were randomly divided into 4 groups (n = 12/group): cobra venom (CV), PGB, EA, and sham-operated (SHAM). The development of pain-related behaviors and spatial learning and memory abilities were measured using video recordings and Morris water maze tests, respectively. The ultrastructural changes of the PNS and CNS were examined using transmission electron microscopy. We also screened the differentially expressed genes and proteins in the prefrontal cortex and hippocampus using ribonucleic acid sequencing and isobaric tag for relative and absolute quantitation techniques, respectively. Data for the behavioral tests and molecular biology were analyzed with a one-way analysis of variance.
The rats in the CV group exhibited long-lasting pain-like behaviors, cognitive deficits, and systemic ultrastructural changes. Both EA and PGB alleviated the chronic pain syndrome, but EA also inhibited the chronic pain-induced cognitive dysfunction and restored normal cellular structures, while PGB was associated with no improvements. Transcriptomic and proteomic analyses revealed marcks, pak2 and acat1 were altered in rats with TN but were adjusted back to baseline by EA but not by PGB.
We examined systemic ultrastructural alterations at different levels of the nervous system; however, the detailed timeline of the damage process was not explicitly delineated. Moreover, the current study provides only preliminary evidence for the neurobiological mechanisms of cognitive impairment resulting from chronic pain. Further research is still necessary (using models such as gene knockout rats and cell cultures) before a detailed mechanism can be postulated.
EA treatment may offer significant advantages when compared to PGB for the treatment of cognitive impairment associated with chronic pain. Moreover, marcks, pak2 and acat1 may be the potential therapeutic targets of EA.
有报道称，神经病理性疼痛与大脑功能和结构异常以及认知缺陷有关。然而，其致病机制仍不清楚。
本研究旨在探讨眼镜蛇毒液诱导的三叉神经痛（TN）大鼠周围神经系统（PNS）和中枢神经系统（CNS）的系统超微结构变化，以及电针（EA）和普瑞巴林（PGB）对 TN 的作用及其机制。
本研究采用大鼠实验设计。
研究地点在中国医科大学航空总医院和北京转化医学研究所的实验室。
雄性 Sprague-Dawley 大鼠随机分为 4 组（每组 n = 12）：眼镜蛇毒液（CV）、PGB、EA 和假手术（SHAM）。通过视频记录和 Morris 水迷宫试验分别测量疼痛相关行为和空间学习记忆能力的发展。使用透射电子显微镜观察 PNS 和 CNS 的超微结构变化。我们还分别使用核糖核酸测序和等重标记相对和绝对定量技术筛选前额叶皮层和海马中的差异表达基因和蛋白。行为学和分子生物学数据采用单因素方差分析进行分析。
CV 组大鼠表现出持久的痛觉样行为、认知障碍和全身超微结构改变。EA 和 PGB 均能缓解慢性疼痛综合征，但 EA 还能抑制慢性痛引起的认知功能障碍并恢复正常细胞结构，而 PGB 则无改善。转录组和蛋白质组分析显示，marcks、pak2 和 acat1 在 TN 大鼠中发生改变，但 EA 可使其恢复正常，而 PGB 则无作用。
我们检查了不同水平的神经系统的全身超微结构改变，但未明确划定损伤过程的详细时间进程。此外，本研究仅为慢性疼痛引起认知障碍的神经生物学机制提供了初步证据。在提出详细机制之前，仍需要进一步研究（使用基因敲除大鼠和细胞培养等模型）。
与 PGB 相比，EA 治疗可能对治疗慢性疼痛相关认知障碍具有显著优势。此外，marcks、pak2 和 acat1 可能是 EA 的潜在治疗靶点。
