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1、分类号：R151密级：无UDC：610学校代码：11065博士专业学位论文MC4R介导神经病理性疼痛的传导机制冯伟指导教师褚海辰教授学位类别在职专业学位博士专业领域麻醉学答辩日期2015年6月6号答辩委员会主席于金贵教授MC4R介导神经病理性疼痛的传导机制中文摘要目的观察HSO14对脊髓背角和脊髓背根神经节（DRG）中NF-κB的影响，探讨MC4R和NF-κB之间关系。方法先予以大鼠鞘内置管成功后，取坐骨神经结扎（CCI）模型，将成熟雄性SD大鼠72只分为四组，假手术组(sham组)，将大鼠坐骨神经暴露后不予任何处理，CCI组，只结扎坐骨神经,H组，CCI后鞘
2、内注射MC4R拮抗剂HS014，10μg/天，持续7天。P组，鞘内注射NF-κB抑制剂PDTC,2ug/天，持续7天。分别于术后3天、7天、14天观察大鼠的热痛阈，免疫组化及Westernblot检测L5-6脊髓背角及其背根神经节MC4R和NF-κB变化。结果CCI组较假手术组术后各时间点热痛阈显著下降（p<0.01），MC4R,NF-κB于CCI术后表达相对sham组明显增多（p<0.01）。H组较sham组热痛阈下降，但比CCI组显著上升（p<0.05），MC4R,NF-κB较CCI组显著下降（p<0.05）。P组较CCI组热痛阈显著上升（p<0.05），
3、MC4R无显著变化而NF-κB显著下降（p<0.05）。结论HS014通过抑制MC4R进而抑制NF-κB的激活而减轻神经病理性疼痛，神经损伤所致神经病理性疼痛中NF-κB可能是MC4R的一个下游信号通路。关键词：HS014；NF-κB；CCI；神经病理性疼痛abstractObjective:Toinvestigatetheinfluencebetweenmelanocortion4recepter(MC4R)andNF-κBinspineandDRGwhichcomefromchronicconstrictinjurymodel,Theninqureinto
4、therelationbetweenmelanocortion4recepterandNF-κB.Methods:MaleWistarwhichareweighing180g-200gwereusedinthisstudy,theneuropathicpainmodelwasinducedbychronicconstrictinjury(CCI)tosciaticnerve.Alltheratswererandomlydividedintofourgroupsaftertheratsweresuccessfullyintrathecallycatheteriz
5、edassignedtoCCIorshamsurgery.Thesefouregroups,shamgroup,onlytoexposethesciaticnerveandnotgetsurgicalligation;CCIgroup,exposethesciaticnervewith4looseligaturesonthesciaticnerveby4-0silksutureat1mmintervals.Hgroup,CCI+HSO14(MC4Rantagonist),10ug/day,forsevendays.groupP,CCI+PDTC(NF-κBin
6、hibitor)2ug/day,forsevendays.MeasuringThermalThresholdrdththbeforeoperationandonthe3,7and14dayafterCCI.ThelevelofNF-κBandMC4Rinlumberspinalanddorsalrootganglion(DRG)wastestedbywesternblotandimmunohistochemistry.Results:ThethermalthresholdinCCIgroupwasobviouslylowerthanshamgroupwitho
7、peration(p<0.01),MC4R,NF-κBexpressionofCCIgroupinDRGandspinalcordwasobviouslyhigherthanshamgroup(p<0.01).IntrathecaladministrationofHSOI4ORPDTCevidentlyblockedtheCCI-inducedhyperalgesiaandHS014decresedtheexpressionofMC4R,NF-ΚBinDRGandspinalcord9(p<0.05)Andatthesametime,PDTConlydecre
8、asedthePDTC(P<0.05)
