在国家自然科学基金资助下，上海交通大学药学院研究生团队最近在乌头生物碱镇痛作用机制的研究中取得重要突破，首次证明乌头生物碱的镇痛作用通过Gs/cAMP/PKA/p38β/CREB信号转导通路，刺激脊髓小胶质细胞释放强啡肽产生，并可与急性神经毒性相分离。阐明相关研究成果的一系列论文近期在Journal of Pain，Journal of Neuroinflammation，Scientific Reports (www.nature.com/articles/srep45056)，Frontiers in Pharmacology和Journal of Ethnopharmacology上发表。

乌头属植物资源丰富、药用历史悠久、在临床上应用广泛。乌头的炮制品称为附子，最早记载于《神农本草经》作为“回阳救逆”之要药应用于中医临床及中药复方制剂中。二萜生物碱是乌头及附子的主要药理活性成分，约有170种，主要可分为C-18型、C-19型和C-20型，其代表药物有乌头碱、草乌甲素、雪上一枝蒿甲素和高乌甲素。乌头、附子及其有效成分乌头生物碱在临床广泛用于治疗类风湿性关节炎疼痛、神经病理性疼痛、腰腿痛、炎性疼痛和癌性疼痛。学术界通常认为，乌头生物碱镇痛与神经元上电压依赖型钠离子通道相互作用有关，与其毒性作用不可分离。

在王永祥教授指导下，李腾飞博士、黄茜博士和孙明丽硕士采用疼痛动物模型、化学生物学、基因沉默和免疫荧光染色等技术，证明乌头生物碱可有效治疗神经病理性疼痛、骨癌疼痛、类风湿性关节炎疼痛和糖尿病疼痛。乌头生物碱镇痛作用系由脊髓背角小胶质细胞释放内源性吗啡样肽-强啡肽所介导，后者作用于胶质细胞-神经元突触后神经元上κ-阿片受体产生镇痛效应，而与钠离子通道的相互作用无关。进一步研究表明，乌头生物碱通过Gs/cAMP/PKA/p38β/CREB信号转导通路释放强啡肽，进而推测乌头生物碱的作用靶点分子为小胶质细胞膜上Gs-蛋白偶联受体，并将其命名为“乌头碱受体”。

上海交通大学研究生团队对乌头生物碱镇痛机制的阐明，颠覆了传统学术概念，为小胶质细胞镇痛和神经保护生物学增添了新内容，亦为乌头生物碱进一步开发和临床使用提供了创新性生物学基础。（来源:生物通）

Molecular signaling underlying bulleyaconitine A (BAA)-induced microglial expression of prodynorphin

Abstract  Bulleyaconitine (BAA) has been shown to possess antinociceptive activities by stimulation of dynorphin A release from spinal microglia. This study investigated its underlying signal transduction mechanisms. The data showed that (1) BAA treatment induced phosphorylation of CREB (rather than NF-κB) and prodynorphin expression in cultured primary microglia, and antiallodynia in neuropathy, which were totally inhibited by the CREB inhibitor KG-501; (2) BAA upregulated phosphorylation of p38 (but not ERK or JNK), and the p38 inhibitor SB203580 (but not ERK or JNK inhibitor) and p38β gene silencer siRNA/p38β (but not siRNA/p38α) completely blocked BAA-induced p38 phosphorylation and/or prodynorphin expression, and antiallodynia; (3) BAA stimulated cAMP production and PKA phosphorylation, and the adenylate cyclase inhibitor DDA and PKA inhibitor H-89 entirely antagonized BAA-induced prodynorphin expression and antiallodynia; (4) The Gs-protein inhibitor NF449 completely inhibited BAA-increased cAMP level, prodynorphin expression and antiallodynia, whereas the antagonists of noradrenergic, corticotrophin-releasing factor, A1 adenosine, formyl peptide, D1/D2 dopamine, and glucagon like-peptide-1 receptors failed to block BAA-induced antiallodynia. The data indicate that BAA-induced microglial expression of prodynorphin is mediated by activation of the cAMP-PKA-p38β-CREB signaling pathway, suggesting that its possible target is a Gs-protein-coupled receptor – “aconitine receptor”, although the chemical identity is not illustrated.

原文链接：http://www.nature.com/articles/srep45056