Oral application of bulleyaconitine A attenuates morphine tolerance in neuropathic rats by inhibiting long-term potentiation at C-fiber synapses and protein kinase C gamma in spinal dorsal horn
Oral application of bulleyaconitine A attenuates morphine tolerance in neuropathic rats by inhibiting long-term potentiation at C-fiber synapses and protein kinase C gamma in spinal dorsal horn
复制标题
口服牛乌头碱 A 通过抑制脊髓背角 C 纤维突触和蛋白激酶 C γ 的长期增强，减弱神经病大鼠的吗啡耐受
DOI：
10.1177/1744806920917242
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发表时间：
2020-04-01
期刊：
影响因子：
3.3
通讯作者：
Liu Xian-Guo
中科院分区：
文献类型：
--
作者：
Mai Jie-Zhen;Liu Chong;Liu Xian-Guo
吗啡经常用于治疗慢性疼痛，而长期使用这种药物会导致镇痛耐受。目前，副作用的预防仍然是一个很大的挑战。草乌甲素（Bulleyaconitine A）是一种来源于草乌属植物的二萜生物碱，在我国已被用于治疗慢性疼痛30多年。在本研究中，我们测试了草乌甲素对吗啡注射（10 mg/kg s.c.，b.i.d.）在腰5脊神经结扎的神经病理性疼痛模型中。我们发现，灌胃应用草乌甲素（0.4毫克/公斤）30分钟前，每次吗啡注射实质上抑制吗啡的抑制作用的机械异常性疼痛和热痛觉过敏的下降。从机制上讲，吗啡注射进一步增强了腰5脊神经结扎诱导的脊髓背角C纤维突触长时程增强，这是一种慢性疼痛的突触模型。灌胃草乌甲素可完全阻断此作用。已经确定，蛋白激酶C γ和脊髓背角中的胶质细胞的活化对于阿片耐受性和神经病理性疼痛的发展是至关重要的。我们发现，吗啡注射加剧了磷酸化蛋白激酶C γ（蛋白激酶C γ的活性形式）的上调，以及腰5脊神经结扎诱导的脊髓背角小胶质细胞和星形胶质细胞的活化，并且灌胃草乌甲素的作用被显著抑制。因此，脊髓长时程增强在C-纤维突触可能是吗啡耐受的基础。口服草乌甲素可能是治疗阿片耐受的一种新的、简单的方法。
Morphine is frequently used for the treatment of chronic pain, while long-term use of the drug leads to analgesic tolerance. At present, the prevention of the side effect remains a big challenge. Bulleyaconitine A, a diterpenoid alkaloid from Aconitum bulleyanum plants, has been used to treat chronic pain in China for more than 30 years. In the present study, we tested the effect of bulleyaconitine A on analgesic tolerance induced by morphine injections (10 mg/kg s.c., b.i.d.) in the lumbar 5 spinal nerve ligation model of neuropathic pain. We found that intragastrical application of bulleyaconitine A (0.4 mg/kg) 30 min before each morphine injection substantially inhibited the decrease in morphine’s inhibitory effect on mechanical allodynia and thermal hyperalgesia. Mechanistically, morphine injections further potentiated the lumbar 5 spinal nerve ligation induced long-term potentiation at C-fiber synapses in the spinal dorsal horn, a synaptic model of chronic pain. This effect was completely blocked by intragastrical bulleyaconitine A. It has been well established that activation of protein kinase C gamma and of glial cells in the spinal dorsal horn are critical for the development of opioid tolerance and neuropathic pain. We found that morphine injections exacerbated the upregulation of phospho-protein kinase C gamma (an active form of protein kinase C gamma), and the activation of microglia and astrocytes in the spinal dorsal horn induced by lumbar 5 spinal nerve ligation, and the effects were considerably prohibited by intragastrical bulleyaconitine A. Thus, spinal long-term potentiation at C-fiber synapses may underlie morphine tolerance. Oral administration of bulleyaconitine A may be a novel and simple approach for treating of opioid tolerance.