AlterationofDescendingModulationofNociceptionduringtheCourseofMonoarth - PDF document

AlterationofDescendingModulationofNociceptionduringtheCourseofMonoarthritisintheRatNicolasDanziger,JeanneWeil-Fugazza,DanielLeBars,andDidierBouhassiraInstitutNationaldelaSanteÂetdelaRechercheMeÂdicaleU-161,75014Paris,FranceDiffusenoxiousinhibitorycontrols(DNIC),whichinvolvesu-praspinalstructuresandmodulatethetransmissionofnocicep-tivesignals,wereinvestigatedatdifferentstagesduringthedevelopmentofadjuvant-inducedmonoarthritisintherat.Afterbehavioralevaluation,recordingsoftrigeminalconvergentneu-ronswereperformedinanesthetizedanimalswithacute(24±48hr)orchronic(3±4weeks)monoarthritisoftheankle.InhibitionsofC-®ber-evokedneuronalresponsesduringandaftertheapplicationofnoxiousconditioningstimulitotheankleweremeasuredtoevaluateDNIC.Theconditioningstimuliconsistedofmechanical(maximal¯exionandgradedpressures)andgradedthermalstimuliandwereappliedalternatelytonormalandarthriticankles.Behaviorally,thetwogroupsofanimalsexhibitedasimilarincreasedsensitivitytomechanicalstimuliappliedtothearthriticjoint(i.e.,anincreasedankle-bendscoreandadecreasedvocalizationthresholdtopressurestimuli).However,theyshoweddifferentelectrophysiologicalpro®les.Intheanimalswithacutemonoarthritis,theDNIC-inducedinhibi-tionsproducedbymechanicalorthermalstimulationofthearthriticjointweresigni®cantlyincreasedatallintensitiescom-paredwiththenormaljoint.Incontrast,inthechronicstageofmonoarthritis,theDNIC-inducedinhibitionstriggeredbyther-malorpressurestimuliweresimilarforbothankles,exceptwiththemostintensemechanicalstimuli.Thisdiscrepancybetweenthebehavioralandelectrophysiological®ndingssuggeststhatinputsactivatedduringchronicmonoarthritismayfailtorecruitDNICandmaythusbefunctionallydifferentfromthoseacti-vatedintheacutestageofin¯ammation.Keywords:nociception;painmodulation;chronicin¯amma-tion;animalmodel;diffusenoxiousinhibitorycontrols;descend-ingcontrols Theoutputofspinalnociceptiveneuronscanbemodulatedbydescending,propriospinal,andsegmentalsystems,whichmaytonicallyorphasicallyinhibitorfacilitatethespinaltransmissionofnociceptivesignals(forreview,seeZieglgaÈnsbergeretal.,1986;Willis,1988;FieldsandBasbaum,1994).Althoughitiswidelyacceptedthattheseendogenousmodulatorysystemsaffectsensationsofpain,thewayinwhichtheyarebroughtintoplayandtheirconsequencesonnociceptivebehaviorhaverarelybeenaddressedinthecontextoftissueinjury(Cerveroetal.,1991;Morganetal.,1991;Schaibleetal.,1991;RenandDubner,1996).Diffusenoxiousinhibitorycontrols(DNIC)aresupraspinallymediatedinhibitorycontrolstriggeredbytheapplicationofnox-iousstimuli.Innormalhealthyrats,spinalandtrigeminalconver-gentneuronsareinhibitedinanintensity-dependentmannerwhennoxiousstimuliareappliedtoheterotopicareasofthebody,i.e.,regionsremotefromtheexcitatoryreceptive®eldoftheneuronunderstudy(LeBarsetal.,1979a,b;DickensonandLeBars,1983;Mortonetal.,1987;NessandGebhart,1991).Inman,heterotopicnoxiousstimuliinhibitsensationsofpainandthespinalnociceptive¯exion(RIII)re¯ex(Willeretal.,1984).Inbothratsandman,thesephenomenaaresustainedbyaloopinvolvingsupraspinalstructuresandendogenousopioidergicsys-tems(LeBarsetal.,1979b,1981;Caddenetal.,1983;Roby-Bramietal.,1987;Willeretal.,1990;Bouhassiraetal.,1993,1995).IthasbeenhypothesizedthatDNICmayfacilitatetheintegrationofpaininformationbythecomplementaryprocessesofsegmentalexcitationanddiffuseinhibition(LeBarsetal.,TheaimofthisworkwastostudywhetherDNICwouldbemodi®edduringthecourseofin¯ammationandtoexaminehowmodi®cationsofthesedescendingcontrolsmightberelatedtopainbehaviorinthecontextofacuteandchronicpain.DNIChavebeenevaluatedpreviouslyinratsrenderedpolyarthriticbyintradermalinjectionsofcompleteFreundadjuvant(CFA)intothetail(Calvinoetal.,1987).However,CFA-inducedpolyarthri-tisisaseverewidespreadsystemicdisease,anditisnotpossiblewiththismodeltocomparedirectlytheeffectsofastimulusonanin¯amedjointandtheeffectsofthesamestimulusonanormalcontralateraljoint.TostudythetemporalevolutionofDNICduringthecourseofchronicin¯ammationwithoutthewide-spreadsystemicconsequencesofpolyarthritis,wereinvestigatedtheseinhibitorycontrolsintheacuteandchronicstagesofCFA-inducedmonoarthritis,amodelofcircumscribed,persistentin-¯ammatorypain(Grubbetal.,1991;Butleretal.,1992).WecomparedDNIC-inducedinhibitionsofconvergenttrigeminalneuronstriggeredbygradedconditioningstimulationofeitherthenormalorthearthriticankleinratswithacuteorchronicmonoarthritis.Ourhypothesiswas(1)thatthesensitizationofnocicepti

veneuronsduringin¯ammationwouldbeparalleledbyanexacerbationofDNICand(2)thatchronicitywouldpossiblybeassociatedwithmodi®cationsofthisphenomenonasaresultofcentralplasticchangesinducedbyprolongedpain.MATERIALSANDMETHODSThestudywasperformedonthreegroupsofSpragueDawleymaleratsweighing300±400gmatthetimeoftheexperiments:acontrolgroupofhealthyrats(12);agroupofratswithacutemonoarthritisoftheankle(16);andagroupwithchronicmonoarthritisoftheankle( ReceivedOct.14,1998;revisedJan.6,1999;acceptedJan.10,1999.WethankDr.S.W.Caddenforadviceinthepreparationofthismanuscript.CorrespondenceshouldbeaddressedtoDidierBouhassira,InstitutNationaldelaÂetdelaRechercheMeÂdicaleU-161,2Rued'AleÂsia,75014Paris,France.Copyright1999SocietyforNeuroscience0270-6474/99/192394-07$05.00/0TheJournalofNeuroscience,March15,1999, 15).Monoarthritiswasinducedbytheintracapsularinjectionof50lofCFAintotherighttibiotarsaljoint.Thisprocedurewasperformedunderbriefhalothane±Nanesthesia,asdescribedpreviously(Butleretal.,1992).TheCFAwaspreparedasfollows:60mgofdeadmycobacte-riumbutyricum(Difco,Detroit,MI)wasaddedtoamixtureofparaf®noil(6ml),9%NaCl(4ml),andTween80(1ml),wasmixedthoroughly,andwasautoclavedfor30minat120ÉC.Theacutemonoarthritisgroupconsistedofanimals24±48hraftertheinjection;theseanimalsshowedacutein¯ammationoftheankle.Thechronicmonoarthritisgroupcon-sistedofanimals3±4weeksaftertheinjectionthatshowedpronouncedswellingoftherightankle.Animalswithpolyarthritisandanimalswithnoorminimalswellingoftherightanklewerediscarded.Behavioraltesting.Onthedayoftheexperiments,animalswereweighed,thecircumferenceofeachanklewasmeasured,andthesensi-tivitytomechanicalstimulationofeachanklewasassessed.Forthispurpose,theanimalsweregentlyrestrainedinasofttowel,allowingaccesstobothhindlimbswhileatthesametimerestrictingmovement.Vocalizationto¯exionandextensionoftheanklewithinitslimitsofmovementwererecorded;foreachpaw,twomanipulationsweremadeineachdirection,andthetotalnumberofvocalizationswasrecorded.Forcepsincorporatingstraingauges,whichwereconnectedtoanampli-®er(HottingerBaldwinMesstechnik,Darmstadt,Germany),wereusedtoevaluatethevocalizationthresholdtopressure.Anincreasingpressurewasdelivereddorsoventrallytotheanklethroughtheforceps,andthevocalizationthresholdwasmeasuredforeachpawbyaveragingthreesuccessivevaluesobtainedat1minintervals.Allobservationswereperformedbyoneoftheauthorstominimizeinter-observerdifferences.Thetestercouldnotbeblindtotheexperimentalgroupbecauseratswithacuteandchronicmonoarthritiscouldbeeasilydistinguished(acertaindegreeofcutaneousdesquamationwascharacteristicofthechronicAnimalpreparationforelectrophysiologicalexperiments.Immediatelyafterthebehavioraltesting,theanimalsweredeeplyanesthetized(2%halothaneina2:1mixtureofNOandO).Atrachealcannulawasinserted,andthejugularveinwascannulated.Theratswerearti®ciallyventilatedatarateof50strokesperminute,withthevolumeofventi-lationadjustedtomaintainanormalacid/baseequilibrium;thiswasassessedwithacapnometer,whichalsomeasuredO,NO,andhalo-thanelevelsthroughouttheexperiment.Heartratewasmonitoredcon-tinuously,andcoretemperaturewasmaintainedat370.5ÉCbymeansofahomeothermicblanketsystem.Theanimalsweremountedinastereotaxicframe,withthehead®xedinaventro¯exedposition.Thecaudalmedullawasthenexposedbyremovingtheoverlyingmusculature,atlanto-occipitalmembrane,andduramater.Aftersurgery,theadmin-istrationofNOwasstopped,andthelevelofhalothanewasreducedto1.2%.Thisanestheticregimenallowsaverystablelevelofanesthesia,underwhichneithermotornorcardiovascularreactionsareobservedduringtheapplicationofstrongstimuli.Recordingoftrigeminalneurons.Extracellularrecordingsfromconver-gentneuronsinnucleuscaudalisweremadewiththeuseofsteelmicroelectrodes(9±12M;FrederickHaer&Co.Inc.,Bowdoinham,ME).Theelectrodewasinsertedontheleftside,1.5±2mmcaudaltotheobexand1.5±2.5mmlateraltothemidline.Thesignalwasledtoadifferentialalternatingcurrentpreampli®er,fromwhereitwasdisplayedonanoscilloscopeandgatedsothatonlysingle-unitactivitywasre-corded.Responsestoelectricalstimulationofthereceptive®eldwerequanti®edbyacomputerizeddata-acquisitionsystem(NotocordInc.,Croissy,France)andstoredforfurtheranalysis.Neuronswereclassi®edasconvergent(i.e.,widedynamicrange)onthebasisoftheirresponsestobothmechanicalandtranscutaneouselectricalstimulationoftheirreceptive®eld.Thepoststimulushistogramswereanalyzedtodistin-guishresponsesattributabletoA-andC-®berinputsbyt

heirlatencies.Onceacellhadbeenidenti®ed,theextentofitsexcitatoryreceptive®eldwasdetermined.Gradedtranscutaneouselectricalstimuli(singlesquarewavepulsesof2msecduration)wereappliedtothecenteroftheexcitatoryreceptive®eldtodeterminetheelectricalthresholdoftheC-®berinput.Onlycellsthatpresentednoseriousalterationsinspikeamplitudeorwaveformduringthecompleteexperimentalprocedurewereconsidered.Onlyoneortwoneuronsperanimalwerecharacterized.AssessmentofDNIC.Theteststimuliconsistedofsequencesofrepet-itiveelectricalstimulation(twotimestheC-®berthreshold,0.66Hz)oftheexcitatoryreceptive®eldsofthetrigeminalneurons.Theheterotopicconditioningstimuliconsistedofmechanicalorthermalstimulationoftheankle.OnlytheC-®ber-evokedresponseswereconsidered.Toobtainasteadydischarge,the®rst30responsesoftheneuronwerenotconsid-ered.Thepoststimulushistogrambuiltfromresponses31±45wasusedasacontrolforthesequence.Theconditioningstimuluswasappliedfor37secfromteststimuli46±70,andthepoststimulushistogrambuiltfromresponses56±70wasusedtoassesstheeffectsoftheconditioningstimulation.TheDNIC-inducedinhibitiontriggeredbyeachheterotopicstimuluswasexpressedasapercentageofdecreaseinthenumberofspikeswithreferencetothecontrolpoststimulushistogram.Thepost-stimulushistogramsbuiltfromresponses71±85and86±100allowedpostconditioningeffectstobemonitoredovertwosuccessive22secperiodsafterthecessationoftheconditioningstimulus.Sequenceswereperformedat5minintervals.Threetypesofconditioningstimuliwereused:¯exionoftheanklewithinitsrangeofmovements;gradedpressureappliedventrodorsallytotheanklewithaconstantintensity(4,8,or16N/cm);andimmersionofthehindpawuptotheankleina44,46,or48ÉCwaterbath.Intheanimalswithacutemonoarthritis,complete¯exionofthearthriticanklecouldbeperformedeasily.Flexionofananklewithchronicmonoarthri-tiswasgenerallylimitedbyankylosisandrequiredmoreforcetoover-comethestiffnessofthejoint.Eachanklewasstimulatedalternately,startingwiththeweakestandendingwiththemostintensestimulus.Consecutivestimulitoeitheranklewerethereforeseparatedby10minintervals.Statisticalanalyses.ResultsarepresentedasmeanSEM.DNIC-inducedinhibitionstriggeredbystimulationofthenormalandarthriticpawswerecomparedwithineachgroupandbetweengroupswiththeuseofANOVAandposthocFisher'sleastsigni®cantdifferencetest.wasregardedassigni®cant.RESULTSBehavioraltestingThecircumferenceofthearthritic(right)anklewasincreasedtoaverysimilarextentintheacuteandchronicmonoarthritisgroups[401and412mmcomparedwith27.00.2and0.3mmforthenormal(left)ankle,respectively].Thenumberofvocalizationsto¯exionandextensionofthearthriticanklewithinitsrangeofmovementswasmaximal(i.e.,fouroffour)forallselectedanimalswithacuteorchronicmonoarthritis.Noanimalwithmonoarthritis(eitheracuteorchronic)vocalizedwhenitsnormalanklewasextendedor¯exed.Thiswasalsotrueforthecontrolanimals.Thevocalizationthresholdtopressureonthenormalanklewasnotsigni®cantlydifferentbetweenthethreegroups,and,aswouldbeexpected,therewasnoleft±rightdiffer-enceinthecontrols(Fig.1).Incontrast,thevocalizationthresh-oldtopressureoftherightanklewassigni®cantlydifferentacrossthethreegroups(0.001).Comparedwith Figure1.Vocalizationthresholdstopressureontheankleobservedinthedifferentgroupsofanimals.,Controlnormalrats;,ratswithacutemonoarthritis(24±48hr);,ratswithchronicmonoar-thritis(3±4weeks).***0.001forcomparisonbetweenrightandleftDanzigeretal.PainModulationandIn¯ammationJ.Neurosci.,March15,1999, controlrats,thevocalizationthresholdtopressureofthearthriticanklewassigni®cantlylowerinboththeacute(0.05)andthechronic(0.0001)monoarthritisgroups(Fig.1).Thisthresh-oldwassigni®cantlylowerinthechronicthanintheacutemonoarthritisgroup(0.05).However,theleft±rightdiffer-enceinthresholdwasnotsigni®cantlydifferentbetweenthesetwogroups.CharacteristicsofthetrigeminalneuronsSixty-twoconvergentneuronswererecordedinthelefttrigeminalnucleuscaudalis(16,24,and22inthecontrol,acute,andchronicmonoarthritisgroups,respectively).Theelectrophysiologicalcharacteristicsoftheseneuronswereverysimilarinthethreegroups:allexhibitedasmallreceptive®eldlocatedunilaterallyonthelipsand/orthemuzzle;spontaneousactivitywasverylow(meanvaluelessthanonespikepersecond)inallthreegroups;thethresholdfortriggeringC-®ber-evokedresponseswassimilarinallthreegroups(6.60.9,5.70.6,and6.00.9mAinthecontrol,acute,andchronicmonoarthritisgroups,respectively);andtheresponsestoC-®beractivationduringthecontrolse-quenceswere

similarinthethreegroups(6.61.0,7.40.9,and1.3spikesperstimulusinthecontrol,acute,andchronicmonoarthritisgroups,respectively).DNICtriggeredby¯exionoftheankleInthethreegroups,¯exionofthenormalankletriggeredvirtu-allynoinhibitionoftrigeminalneuronalactivity.Incontrast,¯exionofthearthriticankleinanimalswitheitheracuteorchronicmonoarthritistriggeredapotentinhibition(Fig.2).Theseinhibitionsweresimilarintheacuteandchronicmonoarthritisgroups(697and686%,respectively;0.001inbothcasescomparedwiththenormalankle).Postconditioningeffects,how-ever,weresigni®cantlymorepronouncedandprolongedintheacutethaninthechronicmonoarthritisgroup(0.05)(Fig.3). Figure3.ComparisonofDNIC-inducedinhibitionstriggeredby¯exionofthearthriticankleinanimalswithacute(blackcolumns)orchronicwhitecolumns)monoarthritis.ThepercentageofinhibitionoftheC-®berresponsesoftrigeminalneuronstriggeredby¯exionofthearthriticanklearerepresentedforeachgroupduring¯exionandintwosuccessive22sec(postconditioning)periodsafterthecessationof¯exion(post-cond1post-cond2).Thesamemaneuverappliedtothenormalankleofarthriticornormalratstriggeredvirtuallynoinhibition(datanotshown).*0.05forcomparisonbetweenacuteandchronicmonoarthritisgroups. Figure2.IndividualexamplesofDNIC-inducedinhi-bitionstriggeredby¯exionoftheankleinaratwithacutemonoarthritisandinaratwithchronicmonoar-thritis.Eachhistogramcorrespondstoasequenceof100stimuliduringwhichC-®ber-evokedresponsesofatrigeminalconvergentneuronwererecordedbefore,during(arrows),andafter¯exionofeitherthenormalorthearthriticankle.,NumberofC-®ber-evoked,time.J.Neurosci.,March15,1999,(6):2394±2400Danzigeretal.PainModulationandIn¯ammation DNICtriggeredbygradedpressureontheankleInhibitionstriggeredbygradedpressureonthenormalanklewereverysimilarinthethreegroups.Inthecontrolrats,inhibi-tionstriggeredbypressureofeithertherightortheleftanklewereverysimilaratallintensitiesofconditioningstimuli(Fig.).Inallcases,inhibitionstriggeredbypressureoftheankleincreasedwiththeintensityofconditioningstimulation.Intheacutemonoarthritisgroup,theDNIC-inducedinhibitionsweremorepronouncedatallintensitieswhenpressurewasappliedtothearthriticankle(0.001)(Fig.4).Inanimalswithacutemonoarthritis,postconditioningeffectswerealsosigni®cantlymorepronouncedwhenpressurewasappliedtothearthriticankle(®rstpostconditioningperiod,0.001;secondpostconditioningperiod,0.01).Incontrast,theanimalswithchronicmonoarthritisdidnotexhibitsigni®cantleft±rightdifferencesintheinhibitionsinducedbypressure(1.39;NS).Inthisgroup,onlythemostintensepressure(16N/cm)triggeredsigni®cantlygreaterinhi-bitionswhenappliedtothearthriticankle(Fig.4DNICtriggeredbythermalstimulationofthehindpawsInhibitionstriggeredbyimmersionofthenormalhindpawinhotwater(44±48ÉC)didnotdiffersigni®cantlybetweenthethreegroups.Inthecontrolrats,theinhibitionswerevirtuallysuper-imposablefortherightandlefthindpaws(Fig.5).Signi®cantleft±rightdifferencesintheDNIC-inducedinhibitionswerefoundonlyintheacutemonoarthritisgroup(0.01)(Fig.5).Comparedwiththenormalpaw,theinhibitionsseenduringimmersionofthearthriticpawweresigni®cantlygreaterat46and48ÉC.Postconditioningeffectswerealsosignif-icantlymorepronouncedonthearthriticsideatthesetempera-tures(0.001forthe®rstpostconditioningperiod).Incontrast,animalswithchronicmonoarthritisdidnotshowanysigni®cantleft±rightdifferencesinDNIC-inducedin-hibitionsduringandafterthermalstimulationofthehindpaws(Fig.5DNIC-inducedinhibitionsofconvergenttrigeminalneuronstrig-geredbygradedconditioningstimulationofeitheranormaloranarthriticanklewerecomparedinratswithacuteorchronicmonoarthritis.Behaviorally,thetwogroupsofratsexhibitedasimilarincreasedsensitivitytomechanicalstimuliappliedtothearthriticjointbutpresenteddifferentelectrophysiologicalpro®les.Intheacutestageofin¯ammation,DNIC-inducedinhibitionselicitedbystimulationofthearthriticjointweresigni®cantlyincreased,regardlessoftheconditioningstimulus.Thisexacer-bationofDNIC®ttedwellwiththebehavioralchanges.Incon-trast,inthechronicformofthedisease,therewasadiscrepancybetweentheelectrophysiologicalandbehavioralresults.Indeed,comparedwiththeacutemonoarthritisgroup,animalswithchronicmonoarthritisshowedarelativedecreaseintheDNIC-inducedinhibitionstriggeredbystimulationofthearthriticjoint.DNICintheacutestageofmonoarthritisInanimalswithacutemonoarthritis,gentle¯exionofthein-¯amedankletriggeredapotentandprolongedinhibitionoftheC-®ber-evokedrespons

esoftrigeminalconvergentneurons.Thisresultisinagreementwiththefactthatinnocuousmovementsbecomenociceptivewhentheankleisin¯amed.DNIC-inducedinhibitionstriggeredbypressureonthearthriticanklewerealsoclearlyincreasedatallintensitiescomparedwiththenormalankle.Thestimulus±responsecurveshiftedtotheleftbutre-mainedparalleltothecorrespondingcurveforthenormalankle,suggestingthattheencodingpropertiesofDNICwerenotim- Figure4.Percentageofinhibition()ofC-®berresponsesoftrigeminalneuronsinducedbygradedpressure(inlogarithmicscale)appliedtoeachankleincontrolanimals()andinratswithacute)orchronic()monoarthritis.*0.05;**0.01;***0.001forcomparisonbetweenrightandleftsides.Danzigeretal.PainModulationandIn¯ammationJ.Neurosci.,March15,1999, paired.TheincreaseinDNIC-inducedinhibitionsduringme-chanicalstimulationofthearthriticanklemayhavebeencausedbyanincreaseintheafferentinputsduringacutemonoarthritis.Inthenormalrat,DNICdependontheactivationofthinmy-elinated(A)andunmyelinated(C)®bers(Bouhassiraetal.,1987),andthemajorityoftheseafferentshavebeenshowntodevelopalong-lastingsensitizationtomechanicalstimuliaftertheonsetofjointin¯ammation(Coggeshalletal.,1983;SchaibleandSchmidt,1985,1988;Griggetal.,1986;forreview,seeSchaibleandGrubb,1993).Changesinthedischargepropertiesofspinalcordneuronshavealsobeendemonstratedduringacutemonoarthritisinstudiesperformedinrats(Grubbetal.,1993),cats(Schaibleetal.,1987;NeugebauerandSchaible,1990),andmonkeys(Doughertyetal.,1992).Grubbetal.(1993),whoseworkisthemostrelevanttoourstudy,showedthat48hraftertheinductionofmonoarthritisbytheinjectionofCFAintoanankle,super®cialordeepdorsalhornneuronswithjointinputsexhibitedlowermechanicalthresholdscomparedwiththoseseeninnormalTheincreaseinDNIC-inducedinhibitionsduringthermalstimulationofthein¯amedpaw®tswellwiththeincreaseinheatsensitivityobservedonthein¯amedhindpawinthe®rstfewdaysafterCFAinjections(Iadarolaetal.,1988;RenandDubner,1996;Jasminetal.,1998).Thissuggeststhatcutaneousafferentsandnociceptiveneuronswithcutaneousinputsmaybesensitizedtoheatduringtheacutestageofmonoarthritis.EvolutionofDNICfromacutetochronicmonoarthritisInagreementwiththebehavioraldata,animalswithchronicmonoarthritisshowedasigni®cantincreaseinDNIC-inducedinhibitionsduring¯exionofthearthriticanklecomparedwiththenormalankle.However,althoughtheconditioningstimulationmighthavebeenstrongerinanimalswithchronicarthritisbe-causeoftheforcerequiredtoovercomethejointstiffness,theDNIC-inducedinhibitionsduring¯exionofthein¯amedankleweresimilarinthetwogroups,andyetthepostconditioningeffectsweresigni®cantlylesspronouncedintheanimalswithchronicmonoarthritis.Inaddition,althoughtheseanimalsshowedacleardecreaseintheirvocalizationthresholdstopres-sureonthearthriticside,DNIC-inducedinhibitionsduringpres-sureonthein¯amedankleweresimilartothoseelicitedfromthenormalankle,exceptwiththemostintensepressure(i.e.,approx-imatelyfourandahalftimesthevocalizationthreshold).Thisdiscrepancybetweenbehavioralandelectrophysiologicalpro®lescontrastswiththedataobtainedinanimalswithacutemonoar-thritis.ItisalsoincontrastwiththeresultsobtainedinratswithCFA-inducedpolyarthritisinwhichlightpressureappliedtothein¯amedareaswasshowntotriggerpronouncedinhibitionoftrigeminalconvergentneurons(Calvinoetal.,1987).However,theincreaseinDNIC-inducedinhibitionsintheseanimalsmaybepartlyrelatedtosystemicmetabolic(Godefroyetal.,1987)orneurological(Reiberetal.,1984)disordersinducedbythedis-ease.Thedifferencesintheresultsobtainedwiththetwomodelsmightalsobeexplainedbythefactthattheaffectedjointsmaybemoreseverelyinjuredinpolyarthriticthaninchronicmonoar-thriticrats.Incontrastwiththeacutemonoarthritisgroup,noleft±rightdifferenceinDNIC-inducedinhibitionswasfoundduringther-malstimulationofthehindpawsinthechronicstageofin¯am-mation.ThisisinaccordancewithrecentdataconcerningtheevolutionofthesensitivitytoheatduringthecourseofCFA-inducedin¯ammationofthehindpawintherat(Jasminetal.,1998).ThecompleteregressionofheathyperalgesiainthechronicstageofCFA-inducedin¯ammationsuggeststhatskinnociceptorsmaybesensitizedonlyforashortperiodaftertheinductionofmonoarthritis,afterwhichnociceptorsinthejointandsurroundingdeeptissuesbecomepreferentiallyinvolved.Thishypothesisisfurthersupportedbytheresultsoftwoelec-trophysiologicalstudiesshowingthatthethresholdtonoxiousheatisnotdecreasedbutincreasedinparabrachialneuronsandinventrobasalthalamicneurons,inthechronicstageofadjuv

antpolyarthritis,comparedwithnormalanimals(GautronandGuil-baud,1982;Matsumotoetal.,1996).Howcanweexplainthedecreaseinpressure-inducedinhibi- Figure5.Percentageofinhibition()ofC-®berresponsesoftrigeminalneuronsinducedbyimmersionofeachhindpawinhotwaterincontrolanimals()andinratswithacute()orchronic()monoar-thritis.*0.05;**0.01forcomparisonbetweenrightandleftsides.J.Neurosci.,March15,1999,(6):2394±2400Danzigeretal.PainModulationandIn¯ammation tionsinthechronicstageofmonoarthritis?Onesimpleexplana-tionisthattheafferentinputinducedbypressuremighthavedecreasedinthechronicstage.Wefoundthatthevocalizationthresholdtopressurewasstillsigni®cantlydecreasedinanimalswithchronicmonoarthritis,butthisresultcouldbeconfoundedbypawmovement.However,electrophysiologicalexperimentshaveshownthatjointafferentsandspinalcordneuronswithjointinputsdisplayasimilardegreeofsensitizationduringacuteandchronicstagesofCFA-inducedmonoarthritis(Birrelletal.,1990;Grubbetal.,1991,1993;McQueenetal.,1991;SchaibleandSchmidt,1996).Thus,therelativedecreaseintheDNIC-inducedinhibitionsthatwasobservedduringpressureofthechronicallyin¯amedanklemaynotsimplybecausedbyareductionintheafferentinputtothespinalcord.Moreover,becausethisrelativedecreasewasspeci®ctothein¯amedankle,itcannotbeexplainedbyaglobaldecreaseofDNIC.Rather,ourdatasuggestthatinputsactivatedduringchronicmonoarthritismayfailtorecruitDNIC.Thisfunctionaldifferencebetweenacuteandchronicmonoarthritismaybeattributabletothefactthatthepopulationsofactivatedneuronsreceivinginputsfromthein¯amedanklemightnotbethesameduringtheacuteandchronicstagesofmonoarthritis.Alternatively,aninhibitorymodulationoftheseactivatedneuronsmayhavedevelopedduringthecourseofmonoarthritisandinterferedwiththespino±bulbo±trigeminalloopsubservingDNIC.Inanycase,thepresentresultssuggestthatchronicin¯ammatoryprocessesinduceareorganizationofthespinaltransmissionofnociceptivesignals,whichmodi®estherecruitmentofDNIC.Furthermore,thedissociationbetweenDNICandnociceptivebehaviorinanimalswithchronicmono-arthritissuggeststhat,inthecontextofchronicpain,mechanismsthatareindependentofDNICmayplayakeyroleintheen-hancementofpainperception.BirrellGJ,McQueenDS,IggoA,GrubbBD(1990)Theeffectsof5-HTonarticularsensoryreceptorsinnormalandarthriticrats.BrJPhar-macol101:715±721.BouhassiraD,LeBarsD,VillanuevaL(1987)Heterotopicactivationof-andC-®brestriggersinhibitionoftrigeminalandspinalconvergentneuronesintherat.JPhysiol(London)389:301±317.BouhassiraD,LeBarsD,BolgertF,LaplaneD,WillerJC(1993)Diffusenoxiousinhibitorycontrols(DNIC)inman.Aneurophysiolog-icalinvestigationofapatientwithaformofBrown-SeÂquardsyndrome.AnnNeurol34:536±543.BouhassiraD,ChitourD,VillanuevaL,LeBarsD(1995)Thespinaltransmissionofnociceptiveinformation:modulationbythecaudalmedulla.Neuroscience69:931±938.ButlerSH,GodefroyF,BessonJM,Weil-FugazzaJ(1992)Alimitedarthriticmodelforchronicpainstudiesintherat.Pain48:73±81.CaddenSW,VillanuevaL,ChitourD,LeBarsD(1983)Depressionofactivitiesofdorsalhornconvergentneuronesbypropriospinalmecha-nismstriggeredbynoxiousinputs;comparisonwithdiffusenoxiousinhibitorycontrols(DNIC).BrainRes275:1±11.CalvinoB,VillanuevaL,LeBarsD(1987)Dorsalhorn(convergent)neuronsintheintactanaesthetizedarthriticrat.II.Heterotopicinhib-itoryin¯uences.Pain31:359±379.CerveroF,SchaibleHG,SchmidtRF(1991)Tonicdescendinginhibi-tionofspinalcordneuronsdrivenbyjointafferentsinnormalcatsandincatswithanin¯amedkneejoint.ExpBrainRes83:675±678.CoggeshallRE,HongKAP,LangfordLA,SchaibleHG,SchmidtRF(1983)Dischargecharacteristicsof®nemedialarticularafferentsatrestandduringpassivemovementsofin¯amedkneejoints.BrainResDickensonAH,LeBarsD(1983)Diffusenoxiousinhibitorycontrols(DNIC)involvetrigeminothalamicandspinothalamicneuronesintherat.ExpBrainRes49:174±180.DoughertyPM,SlukaKA,SorkinLS,WestlundKN,WillisWD(1992)Neuralchangesinacutearthritisinmonkeys.I.Parallelenhancementofresponsesofspinothalamictractneuronstomechanicalstimulationandexcitatoryaminoacids.BrainResRev17:1±13.FieldsHL,BasbaumAI(1994)Centralnervoussystemmechanismsofpainmodulation.In:Textbookofpain(WallPD,MelzackR,eds),pp243±257.Edinburgh:ChurchillLivingstone.GautronM,GuilbaudG(1982)Somaticresponsesofventrobasaltha-lamicneuronsinpolyarthriticrats.BrainRes237:459±471.GodefroyF,Weil-FugazzaJ,BessonJM(1987)Complextemporalchangesin5-hydroxytryptaminesynthesisinthecentralnervoussysteminducedbyexperimentalpolyarthritisintherat.Pa

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