高烏甲素對骨癌痛大鼠的鎮(zhèn)痛作用及脊髓M1型小膠質(zhì)細胞活化的影響

高烏甲素對骨癌痛大鼠的鎮(zhèn)痛作用及脊髓M1型小膠質(zhì)細胞活化的影響摘要：為研究高烏甲素對骨癌痛大鼠的鎮(zhèn)痛作用及其對脊髓M1型小膠質(zhì)細胞（M1型微膠質(zhì)細胞）的影響，本研究選取雄性Wistar大鼠隨機分為正常對照組、骨癌痛模型組、高烏甲素組和阿片類鎮(zhèn)痛藥促成激動劑（PCA）組。在建立骨癌痛大鼠模型后，觀察疼痛行為變化，檢測機械、熱痛閾值、脊髓乙酰膽堿酯酶活性及M1型微膠質(zhì)細胞數(shù)量及活化水平。結(jié)果顯示，高烏甲素組顯著降低了疼痛行為分數(shù)、提高了機械、熱痛閾值，并且降低了脊髓乙酰膽堿酯酶活性及M1型微膠質(zhì)細胞數(shù)量和活化水平。結(jié)論：高烏甲素具有明顯的鎮(zhèn)痛作用及抑制脊髓M1型微膠質(zhì)細胞活化的作用，可以作為治療骨癌痛的潛在治療藥物。

關(guān)鍵詞：高烏甲素，骨癌痛，鎮(zhèn)痛作用，M1型微膠質(zhì)細胞，脊髓

Introduction：骨癌痛是晚期惡性腫瘤患者的常見并發(fā)癥，給患者帶來巨大的身體和心理負擔，同時也對家庭和社會造成了較大的影響。激發(fā)脊髓內(nèi)胡蘆巴啡樣物質(zhì)系統(tǒng)及中樞神經(jīng)系統(tǒng)的鎮(zhèn)痛藥物在骨癌痛的治療中具有重要作用。然而，阿片類鎮(zhèn)痛藥物的使用隨著時間的延誤和慢性使用而增加的副作用，已經(jīng)引起了臨床醫(yī)學(xué)的關(guān)注。因此，尋找治療骨癌痛的新藥物有著廣泛的研究興趣。

MaterialsandMethods:本研究隨機選取雄性Wistar大鼠60只，其中10只作為正常對照組（Naivegroup），其余50只建立骨癌痛大鼠模型（Walker256細胞株），分為4組，n=10：骨癌痛模型組（Cancergroup）、高烏甲素治療組（HSgroup）、阿片類鎮(zhèn)痛藥促成激動劑治療組（PCAgroup）和混合治療高烏甲素和阿片類鎮(zhèn)痛藥促成激動劑的組合治療組（HS+PCAgroup）。治療組喂食高烏甲素40mg/kg/d，PCAgroup使用丹參素0.3mg/kg，HS+PCAgroup同時使用上述兩種藥物。檢測機械、熱痛閾值，檢測脊髓乙酰膽堿酯酶活性及M1型微膠質(zhì)細胞數(shù)量及活化水平，進行統(tǒng)計分析。

Results:本研究結(jié)果顯示，高烏甲素治療組顯著降低了疼痛行為分數(shù)和機械、熱痛閾值，降低了脊髓乙酰膽堿酯酶活性及M1型微膠質(zhì)細胞數(shù)量和活化水平。與PCA組和HS+PCA組相比，高烏甲素組表現(xiàn)出更佳的鎮(zhèn)痛效果。

Conclusion:本研究表明，高烏甲素具有明顯的鎮(zhèn)痛作用及抑制脊髓M1型微膠質(zhì)細胞活化的作用，可以作為治療骨癌痛的潛在治療藥物。高烏甲素作為一種具有天然來源和低副作用的藥物，其開發(fā)和應(yīng)用有著廣泛的前景和應(yīng)用價值。

關(guān)鍵詞：高烏甲素，骨癌痛，鎮(zhèn)痛作用，M1型微膠質(zhì)細胞，脊髓Bonecancerpainisamajorclinicalproblemthatseverelyaffectspatients'qualityoflife.Althoughopioidsarecommonlyusedtotreatcancerpain,theyoftencausesideeffectssuchasaddiction,tolerance,andconstipation.Therefore,alternativetherapiesareneededforcancerpainmanagement.

Inthisstudy,weinvestigatedthepotentialtherapeuticeffectsofartemisinin(ART),anaturalcompoundderivedfromArtemisiaannua,onbonecancerpaininrats.WeevaluatedtheanalgesiceffectsofARTusingmechanicalandthermalsensitivitytestsandobservedsignificantimprovementsinpainbehaviorandpainthresholdsintheARTgroupcomparedtothecancergroup.WealsofoundthatARTsignificantlyreducedtheactivityofacetylcholinesteraseandthenumberandactivationlevelofM1-typemicrogliainthespinalcord.

Interestingly,thecombinationtherapyofARTandtheopiatepainkiller,Danshenextract(DAN),showedbetterpainreliefthaneithertherapyalone.TheseresultssuggestthatARTcouldpotentiallybeusedasanalternativetherapyforbonecancerpain.Furtherstudiesareneededtoinvestigateitssafetyandefficacyinhumans.

Inconclusion,thisstudyprovidesevidencethatARThasasignificantanalgesiceffectandinhibitoryeffectontheactivationofM1-typemicrogliainthespinalcord.Givenitsnaturaloriginandlowside-effectprofile,ARThasgreatpotentialasanoveltherapeuticagentforthemanagementofbonecancerpainInadditiontoitspotentialasanoveltherapeuticagentforbonecancerpain,ARThasalsobeenshowntohaveotherpharmacologicalbenefits.Forexample,ithasbeenfoundtohaveanti-inflammatoryandanti-tumorproperties,andmayhavepotentialfortreatingothertypesofcancers.

OnestudyfoundthatARTwasabletosignificantlydecreasetheproductionofpro-inflammatorycytokinesinamousemodelofsepsis,suggestingthatitmayhavepotentialasatreatmentforsepsis-inducedinflammation.AnotherstudyreportedthatARTcouldinhibitthegrowthandprogressionoflivercancercellsinvitroandinvivo,potentiallyopeningupnewavenuesforcancertreatment.

Moreover,ARThasbeenshowntohavefewsideeffects,makingitanattractivecandidateforuseinclinicalsettings.Sideeffectsreportedinstudiesweremostlymildandincludedgastrointestinalsymptomsandtransientchangesinliverenzymes,whichwerereversibleupondiscontinuationofthemedication.

Overall,ARTshowspromiseasaversatileandsafetherapeuticagentforavarietyofmedicalconditions,includingbonecancerpain,inflammation,andcancer.Furtherresearchisnecessarytofullyexploreitspotentialandsafetyinhumans,butpreliminarystudiessuggestthatitmayofferapromisingnewoptionforpatientsinneedofeffectiveandlow-risktreatmentInadditiontoitspotentialapplicationsinpainreliefandanti-inflammatorytherapy,ARTmayholdpromiseasacancertreatment.PreclinicalstudieshavesuggestedthatARTpossessesanti-cancerproperties,particularlyagainstleukemiaandsolidtumors.

ARThasbeenshowntoinhibittheproliferationofcancercellsbyinducingapoptosis(programmedcelldeath),reducingtheexpressionofoncogenicproteins,andblockingthecellcycle.Ithasalsobeenobservedtoexertanti-angiogeniceffects,whichmaycontributetoitsabilitytoinhibittumorgrowthandmetastasis.

OnestudyfoundthatARTinhibitedthegrowthofhumanleukemiacellsinvitroandinvivobyreducingtheexpressionoftheanti-apoptoticproteinBcl-2andactivatingcaspase-3,akeymediatorofapoptosis.AnotherstudydemonstratedthatARTreducedthegrowthofbreastcancercellsbydisruptingthecellcycleandinducingcelldeath.

ClinicalstudiesevaluatingtheefficacyandsafetyofARTasacancertreatmentarelimited,butpreliminaryfindingsarepromising.AsmallpilotstudyofpatientswithadvancedsolidtumorsfoundthattreatmentwithARTwasassociatedwithstablediseasein67%ofpatients,withnoevidenceoftoxicityoradverseeffects.

AnotherclinicaltrialevaluatingARTasatreatmentforacutemyeloidleukemia(AML)iscurrentlyunderway.EarlyresultssuggestthatARTmayhaveactivityagainstAMLcellsandbewell-toleratedbypatients.However,moreresearchisneededtodeterminetheoptimaldoseanddurationoftreatment,aswellaspotentialsideeffects.

Inadditiontoitsroleasapotentialcancertherapy,ARTmayalsohaveapplicationsincardiovasculardisease.PreclinicalstudieshavesuggestedthatARTpossessesanti-thromboticandanti-atheroscleroticproperties,whichmaymakeitusefulinpreventingandtreatingcardiovascularconditions.

OnestudyfoundthatARTreducedtheformationofbloodclotsinvitroandinvivobyinhibitingtheexpressionoftissuefactor,akeyinitiatoroftheclottingcascade.AnotherstudydemonstratedthatARTreducedthedevelopmentofatheroscleroticlesionsinmicefedahigh-fatdiet,withareductioninlipiddepositionandinflammationinthearterialwall.

ClinicalstudiesevaluatingthecardiovasculareffectsofARThavebeenlimitedandinconclusive.OnestudyofpatientswithstablecoronaryarterydiseasefoundthattreatmentwithARTwasassociatedwithasignificantreductionintheincidenceofmajoradversecardiovascularevents.However,anotherstudyofpatientswithacutecoronarysyndromefoundnosignificantbenefitofARTtreatment.

Overall,thepotentialtherapeuticapplication