α-Asarone Alleviated Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of Spinal Endoplasmic Reticulum Stress in an Liver X Receptor-Dependent Manner
α-Asarone Alleviated Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of Spinal Endoplasmic Reticulum Stress in an Liver X Receptor-Dependent Manner
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α-细辛脑通过以肝脏 X 受体依赖性方式抑制脊髓内质网应激，减轻慢性压迫性损伤引起的神经性疼痛
DOI：
10.1213/ane.0000000000002792
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发表时间：
2018-09-01
影响因子：
5.7
通讯作者：
Zou, Wangyuan
中科院分区：
文献类型：
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作者：
Gui, Yulong;Li, Aiyuan;Zou, Wangyuan
背景：神经病理性疼痛是一种难治性、复杂性疾病。近年来的研究表明内质网应激与神经病理性疼痛密切相关。本研究旨在探讨内质网应激抑制剂α-细辛醚对慢性压迫性损伤（CCI）引起的神经病理性疼痛的影响。在第一部分中，将大鼠分为7组：假手术组、假手术+ α-细辛醚20 mg/kg组、CCI组、CCI +赋形剂组、CCI + α-细辛醚5 mg/kg组、CCI + α-细辛醚10 mg/kg组和CCI + α-细辛醚20 mg/kg组。手术后，每天用α-细辛脑或生理盐水治疗大鼠。测量疼痛阈值，并在第7天取L3-6脊髓样品用于蛋白质印迹和免疫荧光。在第二部分中，大鼠鞘内植入PE-10管，并分为4组：CCI + α-细辛醚20 mg/kg组、CCI + α-细辛醚20 mg/kg +溶剂组、CCI + α-细辛醚20 mg/kg + SR9243组和CCI组。鞘内注射后1h每组5只大鼠分离进行行为学测试。结果：CCI手术可引起明显的机械性痛觉超敏和热痛觉过敏。CCI手术显著诱导了大鼠ER应激（PERK-eIF 2 α、IRE 1 α、CHOP和XBP-1 s）的激活。然而，用20 mg/kg α-细辛醚处理显著减轻CCI诱导的ER应激激活。行为结果显示，在第7天，每天用20 mg/kg α-细辛醚治疗显著减轻了CCI诱导的伤害性行为（机械性异常性疼痛，P = 0.016，95%置信区间，0.645-5.811;热痛觉过敏，P = 0.012，95%置信区间，0.860-6.507）。此外，α-细辛醚诱导肝X受体β（LXR β）和脊髓下游蛋白的表达上调。LXR拮抗剂SR9243可完全抑制α-细辛醚的抗内质网应激和镇痛作用。结论：α-细辛醚以LXR依赖的方式减轻CCI诱导的神经病理性疼痛。α-细辛脑可能是治疗神经病理性疼痛的潜在药物。
BACKGROUND: Neuropathic pain is an intractable and complex disease. Recent studies have shown a close relationship between endoplasmic reticulum (ER) stress and neuropathic pain. Here, we investigated the effect of alpha-asarone, an ER stress inhibitor, on chronic constriction injury (CCI)-induced neuropathic pain.METHODS: Two parts were included in this study. In part 1, rats were assigned to 7 groups: the sham group, the sham + alpha-asarone 20 mg/kg group, the CCI group, the CCI + vehicle group, the CCI + alpha-asarone 5 mg/kg group, the CCI + alpha-asarone 10 mg/kg group, and the CCI + alpha-asarone 20 mg/kg group. After surgery, the rats were treated with alpha-asarone or normal saline daily. Pain thresholds were measured, and samples of the L3-6 spinal cord were taken for western blotting and immunofluorescence on day 7. In part 2, rats were intrathecally implanted with PE-10 tubes and divided into 4 groups: the CCI + alpha-asarone 20 mg/kg group, the CCI + alpha-asarone 20 mg/kg + vehicle group, the CCI + alpha-asarone 20 mg/kg + SR9243 group, and the CCI group. Five rats in each group were separated for behavioral tests 1 hour after intrathecal injection. The rest of them were killed for western blotting on day 7.RESULTS: In this study, CCI surgery significantly induced mechanical allodynia and thermal hyperalgesia. CCI surgery significantly induced activation of ER stress (PERK-eIF2 alpha, IRE1 alpha, CHOP, and XBP-1s) in rats. However, treatment with 20 mg/kg of alpha-asarone significantly alleviated CCIinduced activation of ER stress. Behavioral results showed that daily treatment with 20 mg/kg of alpha-asarone significantly alleviated CCI-induced nociceptive behaviors, on day 7 (mechanical allodynia, P = .016, 95% confidence interval, 0.645-5.811; thermal hyperalgesia, P = .012, 95% confidence interval, 0.860-6.507). Furthermore, alpha-asarone induced upregulated expression of liver X receptor beta (LXR beta) and downstream proteins in the spinal cord. The LXR antagonist SR9243 completely inhibited the anti-ER stress and antinociceptive effects of alpha-asarone in rats.CONCLUSIONS: alpha-Asarone relieved CCI-induced neuropathic pain in an LXR-dependent manner. alpha-Asarone may be a potential agent for treatment of neuropathic pain.