多种异喹啉类生物碱具有显著镇痛与抗炎活性，与其具有影响突触传递与多种离子通道等机制有关，是有前景的非成瘾低副作用镇痛抗炎先导化合物。其镇痛作用与可能的中枢抑制毒性反应的关系也值得探究。本课题利用前期获得的云南地不容异喹啉类生物碱及其结构修饰产物（青风藤碱、克班宁、2Br-克班宁、千金藤碱等），采用中枢/外周疼痛、炎症动物模型与LD50测试，分析其结构与镇痛抗炎活性/毒性关系；筛选高效低毒成分通过疼痛与炎症动物实验、相关因子（BDNF、5-HT、β-EP、PGE2等）及iNOS表达检测，探讨作用机制；通过药动/药效结合模型，比较该成分经皮与口服给药镇痛抗炎起效/持续时间与强度差异，结合血浆及局部组织药物动力学特征，探究局部与全身给药时不同组织药量对药效/毒性作用的规律。为在异喹啉类生物碱中筛选镇痛抗炎药物，探讨镇痛与毒性（假阳性）的关系及机制，选择合理的给药系统增效减毒提供实验与理论依据。

Most of isoquinoline alkaloids displays remarkable activities of analgesia and anti-inflammation, which are related to the mechanism of acting on multi-ion channel and synaptic transmission，and are the prospective lead compounds for developing analgesics and anti-inflammatory drugs with non-addictive and low side-effect. Based on our preliminary study, a series of isoquinoline alkaloids extracted from Stephania yunnanensis H. S. Lo and their structure-modification products (sinoacutine , crebanine, 2Br- crebanine, stephanine, etc.) were applied to compare the activities of analgesia and anti-inflammation, and to characterise the their structure-activity/acute toxicity relationship by using animal models of outer peripheral/central pain, inflammation and LD50 test; Then, 1~2 compounds are screened to investigate the mechanism by taking animal tests of anti-inflammatory and analgesia and by determing the related biochemical factors (BDNF, 5-HT, β-EP, PGE2 etc.) and iNOS expression. By adapting pharmacokinetics-pharmacodynamics model, the differences of the onset /duration time, the effect intensity of anti-inflammatory and analgesia, and the animal pharmacokinetic features of the screened compounds between transdermal and oral administration will be compared, the possible principle of toxicity and activity due to defferent concentration of issue drug when administrated by different routes (local / systemic) will be speculated. The purpose is to provide experimental and theoretical basis for screening anti-inflammatory and analgesic drug candidates from isoquinoline alkaloids, analyzing the relationship and mechanism of analgesic efficacy and toxicity(false positive), providing reasonalbe drug delivery system for enhancing of efficacy and reducing of toxicity.