乌头生物碱镇痛作用及机制研究进展

Research Progress on Mechanisms Underlying Aconitines Analgesia

乌头属植物资源丰富、药用历史悠久、在临床上应用广泛。二萜生物碱是乌头属植物的主要药理活性成分,按结构可分为C-18型、C-19型、C-20型和双二萜生物碱,具有抗炎、镇痛、抗肿瘤等活性。本文旨在综述临床中广泛使用的乌头属药物中几种主要二萜生物碱,包括草乌甲素(C-19型)、雪上一枝蒿甲素(C-20型)、高乌甲素(C-18型)及乌头碱(C-19型)的镇痛作用和机制的研究进展,以及乌头炮制的药理学依据。草乌甲素、雪上一枝蒿甲素、高乌甲素和乌头碱在多种疼痛模型和临床研究中均表现出良好的镇痛作用,其镇痛作用系通过Gs/c AMP/PKA/p38β/CREB信号通路,刺激脊髓背角的小胶质细胞释放强啡肽,随后作用于神经突触后膜神经元上的κ-阿片受体而产生。乌头碱经炮制生成苯甲酰乌头原碱,毒性降低,治疗指数增加。此外,多种乌头属二萜生物碱和乌头提取物均不产生镇痛耐受作用,并能有效抑制吗啡的镇痛耐受,亦与它们的镇痛作用机制有关。

Aconitum has abundant resources and has been prescribed in China and other eastern Asia countries for analgesic,anti-rheumatic and neurological indications for centuries.As the principal active constituents present in Aconitum,diterpenoid alkaloids possess therapeutic activities against inflammation,nociception and tumors,and can be divided into four skeletal categories:C18-,C19-,C20-and bis-diterpenoid alkaloid.In this review,we summarized the research progress on the analgesic effects and the underlying mechanisms of several clinically effective diterpenoid alkaloids in Aconitum including bulleyaconitine(C19-diterpenoid alkaloid),bullatine A(C20-diterpenoid alkaloid)and lappaconitine(C18-diterpenoid alkaloid),as well as aconitine(C19-diterpenoid alkaloid).We also explored the scientific rationale for the Aconitum processing.Bulleyaconitine,bullatine A,lappaconitine and aconitine exhibit potent analgesic effects in a variety of animal models of pain hypersensitivity as well as in clinic.Their antinociception is entirely mediated by stimulation of spinal microglial dynorphin A expression via a Gs/cAMP/PKA/p38β/CREB signal transduction pathway,which then activates the post-synaptic neuronalκ-opioid receptors.Processing of aconitine induces the increase of benzoylaconine,which has lower toxicity and higher therapeutic index.In addition,aconitines or the Aconitum extracts produce antinociception without induction of tolerance and inhibit morphine antinociceptive tolerance,which is also through stimulation expression of spinal dynorphin A.