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1、TheJournalofNeuroscience,July16,2014•34(29):9779–9788•9779NeurobiologyofDiseaseALeptin-MediatedCentralMechanisminAnalgesia-EnhancedOpioidRewardinRatsGrewoLim,1HyanginKim,1MichaelF.McCabe,1Chiu-WenChou,1ShuxingWang,1LucyL.Chen,1JohnJ.A.Marota,1AnneBlood,2HansC.Breiter,
2、3andJianrenMao1MassachusettsGeneralHospital,CenterforTranslationalPainResearch,Departmentsof1Anesthesia,CriticalCare,andPainMedicine,2Neurology,and3PsychiatryandRadiology,HarvardMedicalSchool,Boston,Massachusetts02114Opioidanalgesicsarecommonlyusedinchronicpainmanagem
3、entdespiteapotentialriskofrewarding.However,itremainsunclearwhetheropioidanalgesiawouldenhancetheopioidrewardingeffecttherebycontributingtoopioidrewarding.Utilizingaratparadigmofconditionedplacepreference(CPP)combinedwithanklemonoarthritisasaconditionofpersistentnocic
4、eption,weshowedthatanalgesiainducedbyeithermorphineorthenonsteroidanti-inflammatorydrugibuprofenincreasedCPPscoresinarthriticrats,suggestingthatanalgesiaitselfhadarewardingeffect.However,arthriticratsexhibitedasignificantlyhigherCPPscoreinresponsetomorphinethanibuprof
5、en.Thus,therewardingeffectofmorphinewasenhancedinthepresenceofpersistentnociception,producingaphenomenonofanalgesia-enhancedopioidreward.Atthecellularlevel,administrationofmorphineactivatedacascadeofleptinexpression,glialactivation,anddopaminereceptorupregulationinthe
6、nucleusaccumbens(NAc),whileadministrationofibuprofendecreasedglialactivationwithnoeffectonleptinexpressionintheNAc.Furthermore,themorphinerewardingeffectwasblockedinleptindeficientob/obmiceorbyneutralizingleptinorinterleukin-1intheNAcwithoutdiminishingmorphineanalges
7、ia.Thedataindicatethatsystemicopioidcanactivatealeptin-mediatedcentralmechanismintheNActhatledtotheenhancedopioidrewardingeffect.Thesefindingsprovideevidenceforaninteractionbetweenopioidanalgesiaandopioidrewarding,whichmayhaveimplicationsinclinicalopioiddoseescalation
8、inchronicpainmanagement.Keywords:conditionedplacepreference;leptin;nucleusaccumbens;opioid;pain;rewardIntroductiontivecondit
