基于疼痛抑制行为探讨去甲青藤碱靶向α2-GABAA受体的镇痛效应

疼痛抑制行为测试应用于镇痛效应评价有助于提高镇痛药物研发的预测效度，加快其临床转化进程。我们首次发现去甲青藤碱（青藤碱的体内代谢物）对各种急慢性疼痛模型均有良好镇痛效应，但是能否改善疼痛抑制行为以及它的镇痛作用机制尚不清楚。脊髓苯二氮卓类敏感型含α2亚单位的GABAA受体可能是镇痛药物研发的新靶标，但未被临床证实。我们前期研究以及预实验结果显示去甲青藤碱镇痛作用可能与脊髓α2-GABAA受体相关，且对急性内脏痛诱发的抑制行为具有改善作用。因此，本研究拟建立基于疼痛抑制行为测试的镇痛效应评价方法，进一步深入研究去甲青藤碱的镇痛效应。并基于疼痛抑制行为测试方法，应用不同基因型的GABAA受体α亚单位点突变小鼠，证实靶向α2-GABAA受体是否产生真实镇痛效应且无耐受性产生。在此基础上，我们拟从细胞水平和动物水平验证去甲青藤碱通过靶向作用于脊髓α2-GABAA受体发挥镇痛效应这一科学假说。

The utility of measurement of pain-depressed behaviors in assessment of analgesic effects may improve the predictive validity of analgesic drug development, and accelerate its process of clinical translation. We first found that N-demethylsinomenine (also called SM-315), an active metabolite of sinomenine, exhibits anti-allodynic effects against a variety of acute and chronic pain models. However, whether N-demethylsinomenine can improve the pain-depressed behaviors and the mechanism of its analgesic action is unclear. The benzodiazepines sensitive GABAA receptor containing α2 subunit in spinal cord may be a new target for the development of analgesic drugs, but it has not been proven by clinical practice. Our previous studies and pilot tests suggested that the antihyperalgesia by N-demethylsinomenine may occur through α2-GABAA receptor in spinal cord, and N-demethylsinomenine can improve the depressed behavior induced by acute visceral pain. So, this study was designed to establish and utilize a method for assessment of analgesic effect based on pain-depressed behavior measurement, to further study the analgesic effect of N-demethylsinomenine, and to confirm whether α2-GABAA receptor selective drugs produce true analgesic effect without tolerance liability by using different genotypes of GABAA receptor α subunit-mutated mice. On this basis, this study then intends to perform a series of in vitro and in vivo test to confirm the scientific hypothesis that N-demethylsinomenine exhibit analgesic effect by targeting the α2-GABAA receptor in spinal cord.