α-细辛脑通过依赖肝 X 受体的方式抑制脊髓内质网应激缓解慢性缩窄性损伤诱导的神经性疼痛。
α-Asarone Alleviated Chronic Constriction Injury-Induced Neuropathic Pain Through Inhibition of Spinal Endoplasmic Reticulum Stress in an Liver X Receptor-Dependent Manner.
机构信息
From the Department of Anesthesiology, Hunan Provincial Maternal and Child Health Hospital, Changsha, Hunan, China.
Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
出版信息
Anesth Analg. 2018 Sep;127(3):775-783. doi: 10.1213/ANE.0000000000002792.
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 α-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 + α-asarone 20 mg/kg group, the CCI group, the CCI + vehicle group, the CCI + α-asarone 5 mg/kg group, the CCI + α-asarone 10 mg/kg group, and the CCI + α-asarone 20 mg/kg group. After surgery, the rats were treated with α-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 + α-asarone 20 mg/kg group, the CCI + α-asarone 20 mg/kg + vehicle group, the CCI + α-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-eIF2α, IRE1α, CHOP, and XBP-1s) in rats. However, treatment with 20 mg/kg of α-asarone significantly alleviated CCI-induced activation of ER stress. Behavioral results showed that daily treatment with 20 mg/kg of α-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, α-asarone induced upregulated expression of liver X receptor β (LXRβ) and downstream proteins in the spinal cord. The LXR antagonist SR9243 completely inhibited the anti-ER stress and antinociceptive effects of α-asarone in rats.
CONCLUSIONS
α-Asarone relieved CCI-induced neuropathic pain in an LXR-dependent manner. α-Asarone may be a potential agent for treatment of neuropathic pain.
背景
神经病理性疼痛是一种难治性且复杂的疾病。最近的研究表明内质网（ER）应激与神经病理性疼痛密切相关。在这里，我们研究了 ER 应激抑制剂α-细辛脑对慢性缩窄性损伤（CCI）诱导的神经病理性疼痛的影响。
方法
本研究包括两部分。在第一部分中，大鼠被分为 7 组：假手术组、假手术+α-细辛脑 20mg/kg 组、CCI 组、CCI+载体组、CCI+α-细辛脑 5mg/kg 组、CCI+α-细辛脑 10mg/kg 组和 CCI+α-细辛脑 20mg/kg 组。手术后，每天给予大鼠α-细辛脑或生理盐水治疗。在第 7 天测量疼痛阈值，并取 L3-6 脊髓样本进行 Western blot 和免疫荧光。在第二部分中，大鼠鞘内置入 PE-10 管，分为 4 组：CCI+α-细辛脑 20mg/kg 组、CCI+α-细辛脑 20mg/kg+载体组、CCI+α-细辛脑 20mg/kg+SR9243 组和 CCI 组。每组 5 只大鼠在鞘内注射后 1 小时进行行为测试。其余大鼠于第 7 天处死进行 Western blot。
结果
本研究中，CCI 手术显著诱导机械性痛觉过敏和热痛觉过敏。CCI 手术显著诱导大鼠 ER 应激（PERK-eIF2α、IRE1α、CHOP 和 XBP-1s）激活。然而，20mg/kgα-细辛脑治疗可显著减轻 CCI 诱导的 ER 应激激活。行为学结果显示，每天给予 20mg/kgα-细辛脑治疗可显著减轻 CCI 诱导的痛觉过敏行为，第 7 天（机械性痛觉过敏，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-细辛脑诱导脊髓中肝 X 受体β（LXRβ）及其下游蛋白的表达上调。LXR 拮抗剂 SR9243 完全抑制了α-细辛脑在大鼠中的抗 ER 应激和抗痛觉过敏作用。
结论
α-细辛脑以 LXR 依赖的方式缓解 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一种有潜力的药物。
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