乌头类生物碱反向镇痛药理学研究

Aconitum alkaloids, including aconitine, bullyaonitine A, lappacomtine and bullatine A, have been effectively used for the treatment of chronic pain including cancer pain and neuropathic pain, but its toxicity limits wide use in clinic. It is generally believed that the analgesic property of Aconitum alkaloids could not be separated from its toxicity, as both of which were due to the interactions with voltage-dependent sodium channels located on neurons. However, we discovered that bullyaonitine A produced antinociception via stimulating dynorphin A expression in spinal microglia in our preliminary study. In this proposal, we aim to systemically study antinociceptive effects of aconitine, bullyaonitine A, lappacomtine and bullatine A in a variety of animal models of chronic pain, as well as its induction of antinociceptive tolerance and cross-tolerance to morphine antinociception. We will further illustrate whether all of Aconitum alkaloids induce antinociception by simulation of dynorphin A expression in spinal microglia, which are separated from their toxic effects. Finally, we will illustrate the signal transduction pathway for Aconitum alkaloids to stimulate dynorphin A expression and explore their original target molecules. Our work will provide new and valid theories and knowledge for the hot research fields.

乌头及其有效成分用于治疗多种慢性疼痛，疗效确切，但其毒性作用制约着在临床的广泛应用。一般认为乌头类生物碱的镇痛作用和毒性难以分离，均与神经元上电压依赖性钠离子通道交互作用有关。我们前期实验发现，草乌甲素可能通过刺激脊髓小胶质细胞表达强啡肽产生镇痛作用。我们拟系统研究多种乌头类生物碱（包括乌头碱、草乌甲素、髙乌甲素和雪上一枝蒿甲素）镇痛作用谱、作用特点和作用机制，包括:1)乌头类生物碱的镇痛作用谱和长期给药的镇痛耐受（包括与吗啡的交叉耐受性）以及对吗啡镇痛耐受性的影响；2）乌头类生物碱通过激动脊髓小胶质细胞表达强啡肽发挥镇痛作用，而与公认的钠离子通道无关；从而与毒性作用分离；3）乌头类生物碱促进小胶质细胞表达强啡肽的信号转导通路，并探索其上游靶点分子。本研究结果将有助于支持和扩展乌头类生物碱的疼痛适应症，为阐明乌头类生物碱镇痛作用机制和脊髓小胶质细胞镇痛生物学提供新理论和内容。

本课题中，我们系统地研究多种乌头类生物碱（包括草乌甲素和雪上一枝蒿甲素）镇痛作用谱、作用特点和作用机制，包括:1)草乌甲素和雪上一枝蒿甲素的镇痛作用谱和长期给药的镇痛耐受（包括与吗啡的交叉耐受性）以及对吗啡镇痛耐受性的影响；2）乌头类生物碱通过激动脊髓小胶质细胞表达强啡肽发挥镇痛作用，而与公认的钠离子通道无关；从而与毒性作用分离；3）阐明乌头类生物碱促进小胶质细胞表达强啡肽的信号转导通路草为活化小胶质细胞中的cAMP/PKA 信号转导通路，并证明其上游靶点分子为CREB。本研究结果将有助于支持和扩展乌头类生物碱的疼痛适应症，为阐明乌头类生物碱镇痛作用机制和脊髓小胶质细胞镇痛生物学提供新理论和内容。