芳烷基苯基哌嗪类化合物NH0319的镇痛作用及机制研究

Analgesic effect and mechanism of NH0319,an aralkyl phenyl piperazine compound

目的:研究芳烷基苯基哌嗪类化合物NH0319的镇痛作用及其机制。方法:采用小鼠甩尾实验、大鼠福尔马林实验以及大鼠坐骨神经分支选择性损伤(spared nerve injury, SNI)实验评价NH0319的镇痛作用,采用放射性配体受体结合实验对NH0319的镇痛靶点进行普筛,初步探索该化合物的镇痛机制。结果:化合物NH0319灌胃给药后,能剂量依赖性地明显延长甩尾实验中小鼠甩尾潜伏期,显著减少福尔马林实验中大鼠Ⅰ相和Ⅱ相缩腿舔足时间以及提高SNI模型大鼠的机械痛阈值(P <0.05,P <0.01),表现出较好的镇痛作用。放射性配体受体结合实验表明,NH0319除与5-HT1A受体有较强的亲和力以外(IC50=15.05±3.28 nM),对中枢神经系统中包括阿片类受体(阿片mu受体、阿片kappa受体、阿片delta受体)在内的其它20个受体都没有明显的亲和力(IC50> 1000 nM)。结论:化合物NH0319对小鼠甩尾实验、大鼠福尔马林致痛实验以及大鼠SNI实验都有较好的镇痛效果,其镇痛机制可能与其作用于5-HT1A受体有关,有望开发成抗神经病理性疼痛的新药。

Objective: To study the analgesic effect and mechanism of a novel aralkyl phenyl piperazine compound NH0319. Methods: The analgesic effect of NH0319 was evaluated by tail flick test in mice, formalin test in rats and spared nerve injury(SNI) model in rats. The analgesic target of NH0319 was screened by radioligand receptor binding assay to explore the analgesic mechanism of the compound. Results: Orally administration of compound NH0319 significantly prolonged the tail flick latency in the tail flick test, reduced the time of paw withdrawal and paw licking in phase Ⅰ and phase Ⅱ in formalin test and increased the mechanical withdrawal threshold(MWT) in SNI model rats in a dose dependent manner(P < 0.05, P < 0.01). The binding assay showed that NH0319 had a strong affinity for 5-HT1A receptor(IC50=15.05±3.28 nM), but no significant affinity(IC50 > 1000 nM) for 20 other receptors including opioid receptors(mu receptor, kappa receptor, delta receptor) in the central nervous system. Conclusion: Compound NH0319 has significant analgesic effect on thermal pain in mice, formalin-induced spontaneous pain and SNI-induced neuropathic pain in rats. Its analgesic mechanism may be related to the action on 5-HT1A receptor, the regulation of neuronal excitability and neurotransmitter releasing. It is expected to be developed into a novel anti-neuropathic pain drug.