PICK1抑制剂FSC231的镇痛作用研究

Effect of FSC231,an inhibitor of PICK1 on analgesia in mice

目的研究蛋白激酶Cα相互作用蛋白1(protein interacting with Cαkinase 1,PICK1)抑制剂FSC231的镇痛作用,为开发可用于临床疼痛治疗的PICK1抑制剂提供依据。方法选用40只昆明种小鼠分别于右后掌皮下注射1.4%醋酸溶液、腹腔注射0.6%醋酸溶液制备醋酸致痛模型、左侧足趾注射20μL完全弗氏佐剂(CFA)溶液制备炎症性疼痛模型,左后足趾注射辣椒素溶液制备神经源性疼痛模型。将以上实验动物随机分为4组:对照组和FSC231 3个剂量给药组,每组10只。FSC231 3个剂量给药组分别于造模成功后腹腔注射FSC231 7.83、39.20、78.40μg/kg,给药1次。对照组动物注射等体积的生理盐水。给药1 h后,分别测定小鼠后掌抬腿次数、抑制率、小鼠扭体反应次数、潜伏期、小鼠热痛阈值、脚爪肿胀体积,热缩足反射潜伏期(thermal withdrawal latency,TWL)和机械痛阈值。结果与对照组比较,FSC231可剂量依赖性(7.83~78.40)μg/kg减少小鼠5 min内抬腿次数和6~10 min内抬腿次数,6~10 min内抑制率分别为18.74%、32.59%和45.52%;与对照组比,不同剂量FSC231均可一定程度延长小鼠的致痛潜伏期,但仅高剂量组小鼠的镇痛潜伏期有显著增加(P<0.05);FSC231可剂量依赖性(7.83~78.40)μg/kg减少小鼠的扭体反应次数,其中以高剂量组的作用最为显著(P<0.01)。左侧足趾注射完全弗氏佐剂(CFA)溶液后,小鼠出现舔患足,且患足出现红、肿等现象,表明成功制备了小鼠慢性炎性疼痛模型。给予不同剂量的FSC231后,给药组基础痛阈值较对照组显著升高(P<0.05),但后肢足肿胀体积显著增加(P<0.05)。小鼠左后足趾注射辣椒素后其热缩足反射潜伏期(TWL)和机械痛阈值明显降低,表明成功制备神经病理性疼痛模型。FSC231可剂量依赖性(7.83~78.40μg/kg)升高TWL及机械痛阈值(P<0.05,P<0.01)。结论 PICK1抑制剂FSC231对化学刺激性疼痛、炎症性疼痛以及神经源性疼痛均具有明显镇痛作用,表明PICK1可作为镇痛作用的新靶点,而PICK1抑制剂FSC231可作为镇痛作用的候选药物。

Objective To investigate the pharmacological effects of FSC231,the inhibitor of PICK1 through the establishment of acetic acid induced pain model,inflammatory pain model and neuropathic pain model and provide foundation in treatment of clinical pain. Methods 40 Kunming mices were randomly divided into four groups,after the adaptive feeding for a week,and injected 1. 4% acetic acid solution in the right hind paw of mice,intraperitoneally of 0. 6% acetic acid solution in left toe of mice to prepare acetic acid-induced pain model,injected 20 μL complete Freund's adjuvant(CFA) of left toe to prepare inflammatory pain model,injected capsaicin solution of left rear toe to prepare neuropathic pain model: control group and 7. 83,39. 2,78. 4 μg / kg FSC231 groups,indictors such as counting palm leg raise times,the inhibition rate,writhing response,incubation period,heat pain threshold,paw swelling volume,the value of TWL and mechanical pain threshold were evaluated after 1h. Results Compared with control group,FSC231 could reduce the number of leg raise of mice with dose-dependent manner(7. 83-78. 40) μg / kg in 5 min and the number in 6-10 min,and the inhibition rates in 6-10 min were 18. 74%,32. 59% and 45. 52%. Compared with control group,different doses of FSC231 could prolong the pain incubation period,but only the high-dose group's analgesic incubation period were increased significantly(P < 0. 05); FSC231 could reduce the number of writhing responses in mice with dose-dependent manner(7. 83-78. 40) μg / kg,in which the effects of high dose group were the most significant(P < 0. 01). In inflammatory pain models,each rat often lick its affected feet,the majority of affected feet appeared redness,swelling and other inflammatory performance,which showed that inflammatory pain models were successful made up. After given CFA,the basal pain thresholds were significantly higher than those of control group(P < 0. 05),but the swollen volume of hind legs increased significantly(P < 0. 05). After injected with capsaicin solution in the left hind digit,the TWL and mechanical pain threshold significantly decreased,which showed that neuropathy pain model were successful prepared. FSC231 could rise TWL and the mechanical pain threshold(P < 0. 05,P < 0. 01) with dose dependent manner(7. 83-78. 40 μg /kg). Conclusion FSC231 has obvious analgesic effect including neuropathic pain,inflammatory pain,and chemical irritation pain. These results suggest that PICK1 plays an important role in inflammatory pain and neuropathic pain. It is a new target for pain relief,suggesting that PICK1 is an important analgesic drug targets.