mdl- has no analgesic effect on cci induced neuropathic pain in mice

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1、Molecules2010,15,3038-3047;doi:10.3390/molecules15053038OPENACCESSmoleculesISSN1420-3049www.mdpi.com/journal/moleculesArticleMDL-28170HasNoAnalgesicEffectonCCIInducedNeuropathicPaininMiceNurcanÜçeyler*,LydiaBikoandClaudiaSommerDepartmentofNeurology,UniversityofWürzburg,Josef-Schneider-Str.11,97080Wü

2、rzburg,Germany*Authortowhomcorrespondenceshouldbeaddressed;E-Mail:ueceyler_n@klinik.uni-wuerzburg.de.Received:22February2010;inrevisedform:13April2010/Accepted:26April2010/Published:27April2010Abstract:ThecalpaininhibitorMDL-28710blockstheearlylocalpro-inflammatorycytokinegeneexpressioninmiceafterch

3、ronicconstrictionnerveinjury(CCI).One-hundred-thirteenwildtypemiceofC57Bl/6JbackgroundreceivedCCIoftherightsciaticnerve.Mechanicalpawwithdrawalthresholdsandthermalwithdrawallatencieswereinvestigatedatbaselineandat1,3,and7daysafterCCI.ThreeapplicationregimenswereusedforMDL-28170:a)singleinjection40mi

4、nbeforeCCI;b)serialinjectionsofMDL-2817040minbeforeanduptodaythreeafterCCI;c)sustainedapplicationviaintraperitonealosmoticpumps.ThecontrolanimalsreceivedthevehicleDMSO/PEG400.ThetolerabledoseofMDL-28170formicewas30mg/kgbodyweight,higherdoseswerelethalwithinthefirsthoursafterapplication.Mechanicalwit

5、hdrawalthresholdsandthermalwithdrawallatencieswerereducedafterCCIanddidnotnormalizeaftersingleorserialinjections,norwithapplicationofMDL-28170viaosmoticpumps.AlthoughthecalpaininhibitorMDL-28170inhibitstheearlylocalcytokineupregulationinthesciaticnerveafterCCI,painbehaviorisnotaltered.Thisfindingimp

6、liesthatlocalcytokineupregulationafternerveinjuryaloneisonlyonefactorintheinductionandmaintenanceofneuropathicpain.Keywords:calpain;neuropathicpain;MDL-28170;chronicconstrictionnerveinjury(CCI) Molecules2010,153039IntroductionNerveinjuryinmiceisassociatedwithpainbehaviorandisparalleledbyanincreasein

7、localcytokinegeneexpression.Chronicconstrictionnerveinjury(CCI)isafrequentlyusedneuropathicpainmodel,whichleadstoanearlyincreaseinlocalgeneexpressionofthepro-inflammatorycytokinestumornecrosisfactor-a