Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression
Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression
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Lappaconitine 是一种 C18-二萜生物碱，通过刺激脊髓强啡肽 A 表达，在慢性疼痛中表现出抗过敏作用
DOI：
10.1007/s00213-018-4948-y
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发表时间：
2018-06
影响因子：
3.4
通讯作者：
Wang Yong-Xiang
中科院分区：
文献类型：
--
作者：
Sun Ming-Li;Ao Jun-Ping;Wang Yi-Rui;Huang Qian;Li Teng-Fei;Li Xin-Yan;Wang Yong-Xiang
高乌甲素是一种具有代表性的C18-二萜生物碱，从高乌甲素中提取，在中国作为止痛药已有30多年的历史。本研究以大鼠神经病理性疼痛和癌性疼痛模型评价其抗过敏活性，并探讨其机制。在脊神经结扎诱导的神经病大鼠中皮下注射累积剂量的高乌甲素产生剂量依赖性的机械抗异常性疼痛和热抗痛觉过敏。累积剂量-反应分析显示其E max值为53.3和58.3% MPE，艾德50值为1.1和1.6 mg/kg。高乌甲素单次鞘内给药对机械性痛觉超敏也有剂量和时间依赖性的阻断作用，最大E为66.1%MPE，艾德50为0.8 μg。其多次鞘内给药，每日两次，持续7天，未诱导机械性抗异常性疼痛耐受。皮下注射高乌甲素累积剂量也能剂量依赖性地阻断癌细胞胫骨植入引起的大鼠骨癌痛模型的机械性痛觉超敏反应，其Emax为57.9%MPE，艾德50为2.0 mg/kg。此外，高乌甲素治疗刺激脊髓强啡肽A的表达在神经病大鼠，并在原代培养的小胶质细胞，但不是神经元或星形胶质细胞。鞘内预处理特定的小胶质细胞耗竭剂脂质体包封的氯膦酸二钠，强啡肽A抗体和κ-阿片受体拮抗剂GNTI完全抑制鞘内和皮下高乌甲素诱导的机械性抗异常性疼痛。本研究提示高乌甲素通过直接刺激脊髓小胶质细胞强啡肽A的表达而发挥抗伤害作用。
Lappaconitine is a representative C18-diterpenoid alkaloid extracted from Aconitum sinomontanum Nakai and has been prescribed as a pain relief medicine in China for more than 30 years. This study evaluated its antihypersensitivity activity in the rat models of neuropathic and cancer pains and explored its underlying mechanisms. Subcutaneous injection of cumulative doses of lappaconitine produced dose-dependent mechanical antiallodynia and thermal antihyperalgesia in spinal nerve ligation-induced neuropathic rats. The cumulative dose–response analysis exhibited their E max values of 53.3 and 58.3% MPE, and ED 50 values of 1.1 and 1.6 mg/kg. Single intrathecal lappaconitine dose in neuropathy also dose-and time-dependently blocked mechanical allodynia, with an E max of 66.1% MPE and an ED 50 of 0.8 μg. Its multiple twice-daily intrathecal administration over 7 days did not induce mechanical antiallodynic tolerance. Subcutaneous cumulative doses of lappaconitine also produced dose-dependent blockade of mechanical allodynia in the rat bone cancer pain model induced by tibia implantation of cancer cells, with the E max of 57.9% MPE and ED 50 of 2.0 mg/kg. Furthermore, lappaconitine treatment stimulated spinal dynorphin A expression in neuropathic rats, and in primary cultures of microglia but not neurons or astrocytes. Intrathecal pretreatment with the specific microglia depletor liposome-encapsulated clodronate, dynorphin A antibody, and κ-opioid receptor antagonist GNTI totally suppressed intrathecal and subcutaneous lappaconitine-induced mechanical antiallodynia. This study suggests that lappaconitine exhibits antinociception through directly stimulating spinal microglial dynorphin A expression.
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