Department of Physiology and Pain Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
Guangdong Province Key Laboratory of Brain Function and Disease, Guangzhou, China.
Mol Pain. 2020 Jan-Dec;16:1744806920917242. doi: 10.1177/1744806920917242.
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 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.
吗啡常用于治疗慢性疼痛，而长期使用该药物会导致镇痛耐受。目前，预防这种副作用仍然是一个巨大的挑战。乌头碱 A 是一种来自植物的二萜生物碱，在中国已用于治疗慢性疼痛 30 多年。在本研究中，我们测试了乌头碱 A 对鞘内注射吗啡（10mg/kg，每天 2 次）引起的腰 5 脊神经结扎模型中神经性疼痛的镇痛耐受的影响。我们发现，乌头碱 A（0.4mg/kg）在每次吗啡注射前 30 分钟口服给药可显著抑制吗啡对机械性痛觉过敏和热痛觉过敏抑制作用的降低。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 纤维突触处的长时程增强，这是慢性疼痛的突触模型。这种作用被口服乌头碱 A 完全阻断。蛋白激酶 Cγ（protein kinase C gamma）的激活和脊髓背角胶质细胞的激活对于阿片类药物耐受和神经性疼痛的发展至关重要，这一点已得到充分证实。我们发现，吗啡注射加剧了磷酸化蛋白激酶 Cγ（蛋白激酶 Cγ的一种活性形式）的上调，以及腰 5 脊神经结扎引起的脊髓背角小胶质细胞和星形胶质细胞的激活，而口服乌头碱 A 则可显著抑制这些作用。因此，C 纤维突触处的脊髓长时程增强可能是吗啡耐受的基础。口服乌头碱 A 可能是治疗阿片类药物耐受的一种新的简单方法。
