Triptolide prevents and attenuates neuropathic pain via inhibiting central immune response.
Triptolide prevents and attenuates neuropathic pain via inhibiting central immune response.
复制标题
雷公藤甲素通过抑制中枢免疫反应来预防和减轻神经性疼痛。
作者：
WEI WANG;XIAO-PENG MEI;LEI CHEN;JUN TANG;JIN-LIAN LI;SHENG-XI WU;LI-XIAN XU;YUN-QING LI
背景
目前对神经性疼痛的治疗远不能令人满意。考虑到中枢免疫因子对神经病理性疼痛发病机制的重要贡献，靶向炎症反应被广泛认为是治疗神经病理性疼痛的有效策略。雷公藤甲素在中药治疗炎症性疾病方面有着悠久的历史，并已被证明可以抑制神经胶质细胞释放的细胞因子。
目标
在本研究中，我们测试了雷公藤甲素的全身治疗是否可以预防或减轻与神经性疼痛相关的伤害行为。我们进一步尝试探索雷公藤甲素潜在抗异常性疼痛作用的潜在机制。
研究设计
一项随机、双盲、对照动物试验。
方法
雷公藤内酯醇以单次推注和重复治疗的方式全身给药于脊髓神经结扎（SNL）诱发的神经病理性疼痛大鼠模型。在单次推注治疗实验中，在手术后第 1 天或第 10 天向 SNL 和假手术大鼠给予雷公藤甲素 (30 ug/kg、100 ug/kg、300 ug/kg) 或媒介物一次 (n = 6)。在重复治疗研究中，在第-3天（SNL前3天）至第7天（SNL后7天）期间（每组n = 6）对大鼠进行雷公藤甲素（30 ug/kg、100 ug/kg、300 ug/kg）预防性治疗。另一组 SNL 和假大鼠在术后第 10 天接受雷公藤甲素 (30 ug/kg、100 ug/kg、300 ug/kg) 或在第 11-20 天期间接受媒介物治疗（n = 6 只），以评估已建立的疼痛行为的潜在逆转。用冯弗雷丝测试大鼠的机械异常性疼痛。用免疫荧光组织化学评估脊髓背角星形胶质细胞和小胶质细胞的活化。通过蛋白质印迹分析和实时逆转录聚合酶链反应研究检查丝裂原激活蛋白激酶 (MAPK) 的磷酸化和炎症细胞因子（白细胞介素 6、白细胞介素 1β、单核细胞趋化蛋白 1 和肿瘤坏死因子 α）的表达。
结果
单次推注雷公藤甲素治疗既不能阻止诱导，也不能逆转 SNL 诱导的机械性异常性疼痛的维持。然而，在预防性和介入性范例中，重复施用雷公藤甲素剂量依赖性地抑制神经性疼痛行为。雷公藤甲素阻碍 SNL 诱导的脊髓背角神经胶质细胞（星形胶质细胞和小胶质细胞）的激活，而不影响神经元。此外，雷公藤甲素可以抑制 SNL 诱导的 MAPK 磷酸化。此外，雷公藤甲素可以显着阻断神经性疼痛状态下炎性细胞因子表达的上调。
局限性
雷公藤甲素的直接靶位点（如特定受体）仍有待确定。此外，雷公藤甲素不能完全阻断SNL引起的机械性异常性疼痛。
结论
我们的数据表明，雷公藤甲素可能是通过调节脊髓背角的免疫反应来治疗神经性疼痛的潜在新疗法。
BACKGROUND
Current treatments for neuropathic pain are far from satisfactory. Considering the essential contribution of central immune factors to the pathogenesis of neuropathic pain, targeting inflammatory response is well accepted as an effective strategy for treating neuropathic pain. Triptolide has a long history in traditional Chinese medicine for treating inflammatory diseases and has been proven to inhibit cytokines released from glial cells.
OBJECTIVE
In the present study, we tested whether systemic treatment with triptolide could prevent or attenuate nocifensive behaviors associated with neuropathic pain. We further tried to explore the underlying mechanism of the potential anti-allodynia effect of triptolide.
STUDY DESIGN
A randomized, double blind, controlled animal trial.
METHODS
Triptolide was administered systemically in a rat model of neuropathic pain induced by spinal nerve ligation (SNL) in the single bolus and repeated treatment manners. In the single bolus treatment experiment, triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle was given to SNL and sham-operated rats once on day 1 or on day 10 after surgery (n = 6 each). In the repeated treatment study, prophylactic treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) was given to rats during the period of day -3 (3 days prior to SNL) to day 7 (7 days post-SNL) inclusively (n = 6 each). Another set of SNL and sham rats on postoperative day 10 received treatment with triptolide (30 ug/kg, 100 ug/kg, 300 ug/kg) or vehicle during the period of days 11-20 inclusively (n = 6 each), to assess potential reversal of established pain behavior. Mechanical allodynia of the rats was tested with von Frey filaments. Astrocytic and microglial activation in the spinal dorsal horn was evaluated with immunofluorescent histochemistry. Phosphorylation of mitogen-activated protein kinases (MAPKs), and expression of inflammatory cytokines (interleukin-6, interleukin-1beta, monocyte chemotactic protein-1, and tumor necrosis factor-alpha) were examined with Western blot analysis and real-time reverse transcription polymerase chain reaction study.
RESULTS
A single bolus treatment with triptolide could neither prevent the induction nor reverse the maintenance of SNL-induced mechanical allodynia. However, repeated administration of triptolide dose-dependently inhibited neuropathic pain behavior in both preventative and interventional paradigms. Triptolide hampered SNL-induced activation of glial cells (astrocytes and microglia) in the spinal dorsal horn without influencing neurons. In addition, SNL-induced phosphorylation of MAPKs could be inhibited by triptolide. Furthermore, up-regulated expression of inflammatory cytokines in neuropathic pain states could be remarkably blocked by triptolide.
LIMITATIONS
The direct target site (such as a specific receptor) of triptolide is still to be determined. In addition, triptolide could not completely block the SNL-induced mechanical allodynia.
CONCLUSIONS
Our data suggest that triptolide may be a potential novel treatment for neuropathic pain through modulating immune response in the spinal dorsal horn.
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