脊髓以上多巴胺D2受体介导左旋四氢巴马汀的镇痛作用
脊髓以上多巴胺D2受体介导左旋四氢巴马
汀的镇痛作用
]SSNfY25~-9756ActaPh邮na.Sin中国药理学报]999Aug;20(8):715719
hUp?,.l’1~irnm*,*chiaainfogov~rL..’FrkMica[.715
SupraspinalD2receptorinvolvedinantin0cicepti0n
inducedby1-tetrahydropalmatine
HUJiangYuan,J1NGuo-Zhang~(DepartnwntPharmacolo~,,ShanghaiInstituteofMateriaMedica,
ChineseAcademyofSciences,Shanghai200031,China)
KEYWORDStewahydropalmatine;dopamine
receptors;quinpirole;spiperone;SKF38393;
Sch-23390;naloxoneianfinociception;
non—narcoticanalgesics
ABSTIT
删:Tostudythemleofdoparnine(DAjreceptors
inl-tetrahydropalmatine(1-THP)一inducedantinocicep-
tionM匝TH0DS:einwapedtonealLip)and
intl”athecal”th)injectionswereusedtogivethedrugs.
T}】etail-flicktestwasusedtoassessthenociceptive
threshoIdofrats.REsu1:ByiPinjection.
-
THP(10,20,40mg’kg)aswellasD2receptor
antagonistspiperone(1,2.3I’jproduced
dose-dependentantinociceptiveeffectsonthenocicep-
tionofrats,whilereceptoragonistquinpirole,Dt
receptoragonistSKF38393.andDxreceptorantagonist
Sch-23390showednoantinociceptionMoreover,
l—Tl{orspiperone-inducedantinociceptionwas
markedlyattenuatedbyquinpirole(2,3mg’kg..)but
notSKF3gornaloxone.Ontheotherhand,ith
quinpimle(20,30,40g’kg)alsoinducedadose-
dependentantinociception.whileith?-THP.
spiperone,SKF38393,andSch一23390didnotexhibit
any.antinociceptionFurthermore,曲peronet20,
30,40g’)butnotSch-23390dose—dependently
antugonisedtheanthiociceptioninducedbyquinpimle.
1-THP(,l00,200,300唱’jalsodranuatical-
lyattenuatedthequinpirole—inducedantinociception
withadose—dependentrelationship.C0NCLUS10N:
ProjectsupportedbytheNationalNaturalScienceFoundationof
China.3967t3~29and39600179.andStateKeyLaboratory
ofDmgResearch.K016
CorrespondencetoProfJ1NGuo-Zhang
Plm86216431一l端3.~xt,102Fax86-21—643.
E-mailgzjin@se1%,ershcnc.acell
Received1{)98-儿一10Accepted19994)’202
Activatingthespinalreceptororblockingthe
supraspinalreceptorproducesantinociception.
receptormightbenotdirectlyinvolvedinthe
anthiociception.t-THP(asaantagonist)aswell
asspiperoneproducesantinociceptionviablockingthe
supraspinalreceptor.
INTRODUCTION
TeWahydropalmatine(THP)isthemainactive
ingredientoftheCoo~talisambiguaChainetSch(or
calledCoo,dalisturtshaninoviiBessfYanhuauo.YH
ChouetCCHsu),afamousanalgesicoftraditional
ChinesemedicineIts1evo-enatiomer{1-THP)
possessestheanalgesicactionwithremarkablesedative
manquilizingeffectL一1]}lPhasbeenactedasa
remedyforanalgesicorsedation1istedintheChinese
Pharmacopoeiaandtextbooksofphannacology.
However.theexactanalgesicmechanismof1-THPstil1
remainsunclearuDtonow.Inthel)s.?一THPwas
verifiedasadopamme(DA)receptorantagonistwith
behavioral,biochemical,andelectrophysiologic
experimentsl2,3J.andt-THPhadnoaffinityforoDiate
receptors.Now.averyattractivetaskishowthe
DAantagonisdceffectoff—THPelicitstheanalgesic
actioninclinic.T0elucidutethismechanismnotonly
wil1explaintheanalgesicmechanismof—THP.but
alsowil1understandtheroleofDAnervoussystem
involvedinanalgesia
Muchevidencelmsshowedthatdopaminergic
systemisdirectlyorindirectlyhivolvedintheprocesses
ofnociceptionorantinociceptionIngeneral,most
scholarsagreethattheprocessesofnociceptionatthe
spinalorsupraspinallevelmightbeinfluencedbythe
differentDAreceptorssubtypes’….However.many
repomaboutD1andIreceptorareinvolvedin
nociceptionwerediscordant.Somescholarsdemon—
stratedthatD]andreceptorantagonistscould
716
IsSN雌_.J?56AcbPh棚ac0lSin
Emaltaps@s日ersl~tLcaccn
中国药理学报1999Aug;20(8
Hm/Fax8,5,21_6474.2GX)
enhancetheantinociceptiveeffectofrats,butother
scholarsshowedthatmixedDl/D2orD2agonists
producedadose—dependentantinocicepfiveeffect,while
D.agonistSKF38393wasdevoidofsucheffect.
RecentreportindicatedthatD2agonistquinpirole
prolongednociceptivethresholdL….Therefoie,the
mlethatDlandD2receptorsareinvolvedinnociception
orantinocicepfion11~2dstobeclarifled.Fortiffsaim.
thepresentstudyattemptedtocomparetheeffectsof
2一THP.selectiveDAreceptoragonistsandantagonists
onnociceptionofratsbyintraperitoneal(ip)and
inWathecal(ithjiniection.Inadd晡on,opioidergic
receptorantagonistnaloxonewasalsousedtodetermine
whe山erornotopioidtec?torsinfiuenced血e
antinociceptiveeffectofl-THP.
CH30
CH30
TdHlIlyd】?paI瑚dne
MATERIAI.SANDMETHODS
carriedout48hafteroperation.
DrugsWereinjected
slowlyviatllei山catlleteratavolumeof10.,
uL
followedbvNS1OuLtoflushthecatheter
Tai1nicktestThenociceptivethresholdwas
assessedusingtail—flicktest.Thelalencyforaratto
flickitstailawayfromasouw~ofradiantheatwas
measuredwitllTailFlickTimer1.1(IITCInc,USA)
thi’otl曲applyingnoxiousradiantheattostimulatethe
blackenedundersurfaceofmiddletllirdportionoftlle
taill—flicklatency(TFL)wasrecordedbvtlle
di西”timer.Thebaselinelatency【BLjineachrat
waskeptfrom3.0sto5.0s.ABLwasestablished
bythreeWailsat5.minintervals.TheTFLofWailsat
If)一minintervals协measuredafterinjectionofdrags.
Eachgroupconsistedof6rats.
StafisfiealanalysisTIwasconverted%of
tllemaximalpossibleeffect.11%changeofTFL
wascalculatedaccordingtotlleforl-llala.%C:
(_,TFL—L)/TBL×100%.Data(x?s)were
analyzedbvANOVAfollowedbvBonferronit-test.
H3RESULTS
MaterialsAdultSprague-Dawleyrats(t,
180—20Og)weresuppliedbyShanghaiAnimal
Center,0daeseAcademyofSciences(Grade?,
CertificateNo0O5)l-Tf口(mp141—142?,【JD
一
289.),isolatedbyShanghaiInstituteofMatefia
Med.wasdissolved_nH2S0401mo1.L-..and
adjustedtopH5.5with?OHO.1mol?L,.
SKF38393,Sch一23390,quinpirole,spiperone,and
naloxone,purchasedfromResearchBiochemicals
IntemationalCompanyfUSA).wemdilutedwitll
normalsaline(NS).
1ntrathecal(ith】injectionofanle,s
catheterswereinstalledintothelumbarsubarachroid
spaceforithinjectioneflv,ratswem
anesthetizedwi山sodiumpentobarbital30mg?kg,a
PE一10polyethylenecatheterof75IraTllongwas
implantedintotllelranbarenlargementoftllespinal
cord.Thoseratsshowinganymotordeficitresulting
fromtllesurgicalprocedurewereexcludedfrom山e
study.ExperimentswithithinjectionofdrugswGiv.
Anfinecicepfiveeffectsofl-T日andn
receptorantagonistspiperonebyipinjection
AdmiifisWafionofipI-THP(10.20,40mg’kg)
andD2receptorantagonistspiperone(1,2,3mg’
k2-.)producedsignificantanddose—dependent
anfinociceptiveeffectsollthenociceptionofrats,while
ipD2receptoragonistquinpirole(2.3Ingj,Dl
receptoragonistSKFB8393(2,3mg’)and
antagonistSch-23390【2,3mg’kg)showedno
antinocicepfionAdministrationofiptllesamevolume
ofvehicleorNSalsoexhibitediloeffectollnociception
ofrats(T曲1,Fig1).
D2receptoragonistquinpiroleattenuating
theantlnocicepfioninducedbyipl-THPor
spiperoneToevalttatethepossibleinteractionof
1-THP-induc酣antinociceptionwi山DAandopioidergic
receptOrs,quinpirole,SKF38393,andnaloxonewere
ipected5millafaripl-THP(40mg’kg..)or
spiperone(3mg’kg).Quinpirole(2.3g’)
producedadose—dependentantagonisticeffecton
l-THE-orspipemne—inducedantinociception,while
SKF38393【2,3mg’kg),naloxone【2,4mg?
-.),andNSexhibitednoeffectolltheandnociceg-
ISSN02?_956ActaPha力na?lSin
E—mailaps@Ne/~,g.r.shcnccR
中国药理学报1999Aug;20(8l
Phn/Fax8B0l一6474一蚴7】7
Tab1.EffectsofI-THP,DAreceptoragonistsand
antagonistsontail?flicklalcy(TFL)ofm谯.
DrugsDose%change
ofTFL
1p
DIagonistSKR393
DIantagonistSch-23390
a呈嘶qLdnpim|e
antagonistspipemne
NS
一
_rHP
Vehicle
一
_rHP40mg’kg
+quinpirole
+NS
+SKF38393
+na]OXOllle
ith
DtagonistSKR畦93
DIantagonistSch.23390
agonistquinpimle
D2antagonistspipemne
NS
一
_rHP
Vehicle
Qui~pim]e40JIg’
+st~pemne
+NS
+一_rHP
+vehicle
+Sch-23390
23mg’..
2,3mg’..
2.3mg’kg一.
l,2,3mg’kg..
0.4『nIl
l0.?.40mg’kg
0.4mL
2,3mg’kg’
04mL
2,3mg’kg一
2,4mg’kg’
?,40旭’
?.40g’
?,3o,40g’
?,40g’
l0L山
1O0,’200,300,
ug’kg’
l0L山
?.30,40JIg’
10lfL
200,300;zg’kg.
l0uL
20,40g’..
十:denotesignificantincreaseofTFL:一:denote?changeof
TFL;9:denolesigniticantantagonisticefl~t;+:denote?
antagonisticeffect
tioninducedbyf-n{Porspiperone(Tabl,Fig1).
Antinociceptiveeffectsofithnreceptor
agonlstquinpiroleatthespinallevel
Administrationof|山agonistquinpirole(舶,3O,4o
g’..)inducedasi~cantanddose-dependent
antinociception,but山l-THP【100,200,3O0g’
kg).D2antagonistspiperone(20,40gkg),Dl
agonistSKF38393【20,40g’kg),andDI
antagonistSch-23390(20,40g’kg)showedno
effectonnociception.ThesameadminisWalionof
vehicleorNSalsoexhibitednoeffectonnociception
(Tab1,Fig2).
Dzreceptorantagonistspiperoneand
1.THPantagonizingithquinpirole-induced
antinociceptionatthespinallevelToexplore
whetherquinpirole-inducedantinociceptionismediated
鲁
8
Time,mill
ng1.1~rcentagedqgesofTFLafteripl-THP
【A),bP<0.05.甲<0.01借vehicle;andipD2
receptoragomstquinpirolea恤nl】atedanllnoclcep?
doninducedbipI-THPcB】.n=6.?s.
Arrowdenotestimeatwhichipqulnplrole删NS.
中<0.05.rP<0.01珊I-THP.
viaDxorrecel~orsatthespinallevel,Dlantagonist
Sch?23390andantagonistspiperonewere|山injected
5minafterithquinpirole(40Pg.kg)respectively.
Qninpirole—inducedantinociceptionwasdose-dependent—
lyantagonisedbyspipemne(20,30,40g’kg)but
notSch-23390(20,40gkg)orNSMoreover,
曲l-THP(200,300/*g’kg)alsoexhibited.皿
antagomsficeffectagainstquinpirole-inducedanti?
nocicepfionwithadose—dependentrelationship,while
itl1vehiclehadiioantagonisticeffect(Tabl,Fig2).
DISCUSSION
Inthepresentexperiments,thenociceptive
thresholdofratswasmeosumdwithtai1-flicktest
applyingnoxiousradiantheatstimuli.Theevidences
ofl-THP,D1andagonistsorantagonistsithected
directlyintospinallevelhavetx’esentedaconception
thatatthespinalonlyagonistquinpirole,butRot
砷蚰蚰肿曲如钟0椰种”帅鲫神蛐如
7】8
ISSN2醋-977~PhmacSm
E-m~l?s@??sI1acn
中画药理学报l9Ag;2OlB)
Pt?Faxt36.21.6429
苫
目
巴
Time/min
Fig2.Percentagedltng~iofTFLafterithl-THP
(A);andithl-THPattenuatedantinociception
inducedbyithreceptoragomstquinpirole(B).
n=6.髯?s.Arrowdenotestimeatwhichith
I-THPorvehicle.bp<O.05.<O.01quinpirole.
-
nlP,D2antagonist,Dtagonistandantagonist,
participatesinantinocicepfion.Moreover,ourexperl’
mentstillshowedthatithantagonistspipeloneand
f.11?butnotDlantagonistSch-23390COUldblockthe
antinociceptioninducedbyagonistquinpimle
TheresultsaIesimilartosomereportsindicatingthati山
DAagonistinhibiiedthespinalnociception,andi山
apomorphinecouldprolongthe1’FLofrats,.一】l’.
Obviously,OUrfindingsstronglysupporttheideathat
Dreceptorisinvolved-n山emodulationofnociception
transmission,madthatactivatingthespinalD2receptor
contributstotheantinociception.Thus,itispresumed
thatanalgesicsiteofl-?口isriotatthespiI1allevel
duetoits13,2antagonisticaction.
Ontheotherhand,thepresentstudyresultssti11
showedthatipDe.
antagonistspipemnecouldinducethe
antinociception,whileipD2agorlistquinpirdiehadno
antinociception.Tmsfactindicates山altheperipheral—
lyadministrationofspipemneproducestheantinocicep—
tionat山esupraspinallevelbutnotat山espinalleve1,
jtsactionsitesofantinociceptiona佗1LIStoppositeto
thoseofDzagonistqunipimleTheresuitsaresimilar
tofilepreviousreport’orrecentreport,.More—
over,ipspiperone-inducedantinuciceptionwasmarked-
lyattenuatedbyipagonistquinpimlebutnotipDt
agonistSch-T3390.Inotherwords,thepresentresults
indicatethatreceptorinvolvedinantinociceptionjs
dependent0ntheactionsites.bo血activatingthespinal
D2receptorandblockingthesupraspinalD2receptor
exerttheanalgesiceffect.
Astothelx~sibleroleofD1receptorin
nociceptionorantinociception,OlWexperimentshowed
thatiporit11Dtagonistandantagonistdidnothaveany
antinociceptionOurobservationisagreementwith
otherreport-’.111eresultssuggestthatDtreceptor
mightbenotdirectlyinvolvedintheantinociception
I-THP,anovelDAreceptorantagonist,which
actsasananalgesicdrug.alsoproducedantinociceptive
effectbyipbutnotith.Interestingly,itht-THPcould
alsodramaticallyattenuatetheantinociceptioninduced
byithquinpirole.ThiseffectW~LSverysimilartoD2
antagonistspiperone.Itsuggeststhattheanalgesic
effectofl-THPismediatedbyblockingthesupraspinal
receptorInaddition,theresultthatipf-THP-
Inducedantinociceptionisnotaaenuatedbynaloxone
indicatesopioidergicreceptorsnotdirectlyinvolvedin
theantmociceptionoff-THP.
However.inthepresentstudy.itisdi街cultto
asc~laintheexactactionsitesofl-THPinthebrain.
Owingtothat?11?solubleintheacidicn~tnTlis
difficulttobeadjustedtopH74forintmoerebmventri—
cularoFIntro-nucleus~iection.wededu.ethatf-?{P—
inducedantinociceptionismediatedbyblockingthe
supraspInalD2receptorbasednotonlyonpresentstu
results.butalsoontheotherresultsL.Inprevious
experiment,usingFosproteinimmunohistochemistry
technique.wehavedemonstratedthatl-THPactedon
thesWiatum,accumbensnucleus,andsensofimotor
cortext4J
.
Asweallknow,Fosprotein,aproductof
immediateearlygenec-fosexpression,isamarkerof
neuronalactivityfortracingneuronalactionsites
Furthermore,f-THPshoweditsanalgesiceffectagainst
formalin-painbasedonitsenhancingtheactb~ityof
brainsterndescendingmodulationsystemTherefore.
thesedatasupportthatfileanalgesicsitesoff-THPare
atthesupraspinallevel
Inconelusion.f-THPactsasaantagonist
Involvedinantinuciceveeffectbyblocking山e
0{鲫曲钟栅仲0
ISSN0253-9756AbPharmacolSin中国药理学报1999】】g;20(8
E-rmilaps@set~,ershcncalPlm/Fax86-21~474—2629
supraspinalreceptorannmOi1painandacuptmCoareanalgesiainrats
ActaPhysiolSin]998;50:49一.
13Fleetwood-WalkerSM,HopePJ,MitchellRAntinoci—
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脊髓以上多巴胺D2受体介导左旋四氢巴马汀的
镇痛作用
,
(中国科学院上海药物研究所,上海2013031,中国)
关键词璺氢里里丕里堕至垡;喹吡罗;
螺哌隆;SKF38393;Sch.23390;纳洛酮;
抗痛效应;非麻醉性镇痛药
目的研究DA受体与左旋四氢巴马汀(1-THP)镇
痛作用的关系,以阐明l-THP的镇痛机制.方法:
腹腔(ip)与鞘内()给药,以大鼠甩尾反应观测热
伤害性致痛阐.结果:ipl-THP或受体拮抗剂
螺哌隆产生剂量依赖性镇痛效应,并能被受体
激动剂喹吡罗翻转,但不被纳洛酮翻转.而
l-THP或螺哌隆无镇痛效应,但它们能拮抗喹
吡罗引起的镇痛效?
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