The Bad Taste of Medicines - Overview of Basic Research On Bitter Taste PDF

6/28/2016
TheBadTasteofMedicines:OverviewofBasicResearchonBitterTaste
ClinTher.AuthormanuscriptavailableinPMC2014Aug1.
Publishedinfinaleditedformas:
PMCID:PMC3772669
NIHMSID:NIHMS509596
ClinTher.2013Aug35(8):12251246.
Publishedonline2013Jul22.doi:10.1016/j.clinthera.2013.06.007
JulieA.Mennella,PhD,AlanC.Spector,PhD,DanielleR.Reed,PhD,andSusanE.Coldwell,PhD
JulieA.Mennella,MonellChemicalSensesCenter
ContributorInformation.
CorrespondingAuthor:JulieA.Mennella,PhD,Phone:2675194880,Email:mennella@monell.org
CopyrightnoticeandDisclaimer
Publisher'sDisclaimer
Thepublisher'sfinaleditedversionofthisarticleisavailableatClinTher
SeeotherarticlesinPMCthatcitethepublishedarticle.
Abstract
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Background
Manyactivepharmaceuticalingredientstastebitterandthusareaversivetochildren,aswellasmanyadults.
Encapsulationofthemedicineinpillortabletform,aneffectivemethodforadultstoavoidtheunpleasanttaste,is
problematicforchildren.Manychildrencannotorwillnotswallowsoliddosageforms.
Objective
Thisreviewhighlightsbasicprinciplesofgustatoryfunction,withaspecialfocusonthescienceofbittertaste,
derivedfromstudiesofanimalmodelsandhumanpsychophysics.Wefocusonthesetofgenesthatencodethe
proteinsthatfunctionasbitterreceptors,aswellasthecascadeofeventsthatleadtomultidimensionalaspectsof
tastefunction,highlightingtherolethatanimalmodelsplayedinthesediscoveries.Wealsosummarize
psychophysicalapproachestostudyingbittertasteinadultandpediatricpopulations,highlightingevidenceofthe
similaritiesanddifferencesinbittertasteperceptionandacceptancebetweenadultsandchildrenanddrawingon
usefulstrategiesfromanimalmodels.
Results
Medicineoftentastesbitter,andbecausechildrenaremorebittersensitivethanareadults,thiscreatesproblemswith
compliance.Bitterarisesfromstimulatingreceptorsintastereceptorcells,withsignalsprocessedinthetastebud
andrelayedtothebrain.However,therearemanygapsinourunderstandingofhowbesttomeasurebitternessand
howtoameliorateit,includingwhetheritismoreefficientlyaddressedatthelevelofreceptorandsensory
signaling,atthelevelofcentralprocessing,orbymaskingtechniques.Allmethodsofmeasuringresponsivenessto
bitterligandsinanimalmodels,throughhumanpsychophysics,orwithelectronictongueshavelimitations.
Conclusions
Bettertastingmedicationsmayenhancepediatricadherencetodrugtherapy.Sugars,acids,salt,andother
substancesreduceperceivedbitternessofseveralpharmaceuticals,andalthoughpleasantflavoringsmayhelp
childrenconsumesomemedicines,theyoftenarenoteffectiveinsuppressingbittertastes.Furtherdevelopmentof
psychophysicaltoolsforchildrenwillhelpusbetterunderstandtheirsensoryworlds.Multipletestingstrategieswill
helpusrefinemethodstoassessacceptanceandcompliance/adherencebyvariouspediatricpopulations.Research
involvinganimalmodels,inwhichthegustatorysystemcanbemoreinvasivelymanipulated,canelucidate
mechanisms,ultimatelyprovidingpotentialtargets.Theseapproaches,combinedwithnewtechnologiesandguided
byfindingsfromclinicalstudies,willpotentiallyleadtoeffectivewaystoenhancedrugacceptanceandcompliance
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772669/
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inpediatricpopulations.
Keywords:bittertaste,flavor,children,medicines,animalmodels,receptors,psychophysics,genetics,palatability
1.Introduction
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Mostchildrenatsomepointintheirlivesareprescribedmedicine.Somerefusetotakeit,andtheyandtheirparents
suffertheconsequences.Althoughchildrenaresubjecttomanyofthesameailmentsanddiseasesasadultsandare
treatedwiththesamedrugs,mostdrugs(nearly75%)availableintheUnitedStateslackFoodandDrug
Administration(FDA)approvedpediatricformulationsandthereforedonothavelabelinginformationabout
pediatricsafetyandefficacy.1Thelackofchildfriendlyformulationsleavesanestimated40%oftheworlds
childrenatincreasedriskforavoidableadverseevents,suchassuboptimaldosing,lackofadherencetomedication
regimens,andreducedaccesstonewmedicines.2AlthoughrecentlegislationintheUnitedStatesandEuropean
Unionhascreatedincentivesfortestingdrugsinthisspecialpopulation,3thisprocessisconfoundedbythe
requirementthattheformulationbesuitableforthepediatricpatientpopulationactuallyacontinuumofmany
smallerpopulations,suchaspreterminfants,terminfants,infantsandtoddlers,preschoolers,schoolagechildren,
andadolescents.2
2TheProblem:AMatterofTaste
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Acentralchallengeofadministeringmedicinetochildrenisamatteroftastedrugs,bytheirverynature,often
tasteunpleasant,withbittertasteaprimaryculprit.Morethan90%ofpediatriciansreportedthatadrugstasteand
palatabilitywerethebiggestbarrierstocompletingtreatment.2
Mostdrugsworkbyinterferingwithphysiologicalprocesseswithincells,somedicineshavethepotentialtobe
toxicwheningestedinsufficientquantity.Bittertasteisthoughttohaveevolvedasadeterrentagainstingesting
toxicsubstances,4whichmayexplainwhymanydrugstastebitter.Thebasicbiologyofthechild,asreviewed
here,explainswhychildren(andadults)rejectbittertastingdrugs.Infact,bittercompoundsareeffectiveagentsin
deterringpediatricpoisoningswhenusedinconjunctionwithotherpreventivemeasures,suchaschildresistant
closures.5
Althoughmanysolidoraldosageforms(e.g.,pills,tablets)havetheadvantageofmaskingorencapsulatingbitter
tastes,suchmethodsareineffectiveformanychildrenbecausetheyoftencannotorwillnotswallowpillsortablets.
Thecutoffforneedingliquidformulationstypicallyisbetween6and8yearsofage,6butolderchildren(and
teenagersandadults)varygreatlyintheirabilitytoswallowtabletsandcapsules.7,8Inaddition,fixeddosesare
impracticalbecausethedosageoftenvariesaccordingtothesizeofthechild.ThePhysicianDrugandDiagnosis
Auditrevealedthat6yearoldswerefourtimesaslikelyas16yearoldstonottaketheirmedicationsasoral
solids.2
Drugsusuallyareadministerednotalonebut,rather,aspartofformulationsthatareineitherliquidorsolidform.
Liquidformulationsarecomplexmixturescontainingmanyothercomponentsbesidestheactiveingredients
excipientsinclude,butarenotlimitedto,bulkmaterials,flavorings,sweeteners,buffers,preservatives,andcoloring
agents.9Becausemaskingthebittertasteofmedicationsisamajorchallengeinformulatingliquidmedications,
drugsareoftencombinedwithmorepleasanttastingcompounds,forexample,sucrose,highintensitysweeteners,
andflavorspopularwithchildren,suchasbubblegum.Addingbothsugarsandacidstomedicationformulations
reduces,butdoesnotcompletelyeliminate,thebitternessofdrugs.10However,frequentuseofsucrosesweetened
medicineshasbeenlinkedtodentalcariesinchildren.1115Thisconcernisresponsible,inpart,forthegeneral
decreaseinsugarcontentinprescriptionmedicationsinrecentdecades.16,17
Incontrast,acidsremaininfrequentuseinmedicineformulationstoimproveflavorandtomaintainchemical
stability.18Childrenlikemoreintensesournessthandoadults,19soloweringthepHincreasesthepalatabilityfor
children,probablymoresothanforadults,andcancontributetobittertastemasking.Usingbufferingagentsto
adjustpHintotheacidicrangealsoincreasesthestabilityofmedicationsotherwisepronetohydrolysisinliquid
formulations.20However,addingacidstomedicationshasthepotentialtocausedentalerosion(atpH<5.5).18
Abouthalfof97pediatricmedicationformulationsusedregularlyandoverthelongtermbychildrenhavean
endogenouspHbelow5.5andthusarecapableofdamagingtoothenamel.18Citricacidwasthemostfrequently
usedacid,whichraisesconcernsbecausecitricacidhasbeenlinkedtotootherosionduetoitsabilitytodissolvethe
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hydroxyapatiteoftoothenamelanddentin.21,22
Theneedforliquidsforsomechildrenmaybebypassedbynewermodalitiesfordeliveringmedicationsfor
children.However,solidoralminitabletswererefused,spatout,orchewedbyhalfofchildrenyoungerthan5
years,23andchewablesandmeltingtabletstriggerbittertasteresponses,limitingthecompoundsamenabletosuch
formulations.Inaddition,newresearchsuggeststhattheingestionofbittercompoundsmayalsoactinthegutto
elicitnausea.24Whetherchildrensencounterswitharelativelynoveltastingmedicationfollowedbynauseacan
resultinalonglastinglearnedaversiontotheflavor25isanimportantareaforfurtherresearch.
Althoughliquidformulationsareoftenthepreferredformoforaldeliveryforinfantsandyoungchildren,2,20,26the
vastmajorityofdrugsarenotcommerciallyavailableinthisform.26Theneedforliquidformulationsisexpectedto
risemostnewlyapproveddrugsarenotyetlabeledforuseinpediatricpatients,andanappropriateformulation
usuallyisnotavailableunlessthedrugisapprovedforthatpopulation.26
Inthisarticle,wedrawknowledgefromthechemicalsensesliterature,withemphasisonbittertasteresearch
involvinganimalmodelsandonrecentdevelopmentsinthepsychophysicalassessmentoftasteresponsivenessin
children(seeMennellaandBeauchamp200827foranearlierreview),tobetterunderstandthenatureofbitterness
andsuggestfurtherwaystomakemedicationsmoreacceptabletothepediatricpopulation.Wefocusonbittertaste
butacknowledgethatothersensoryattributes(e.g.,texture,sourness,orbadodors)alsoplayaroleincompliance.
Wereviewthesetofgenesthatencodefortheknownproteinsthatfunctionasbitterreceptors,aswellasthe
cascadeofeventsthatleadtomultidimensionalaspectsoftastefunction,highlightingtherolethatanimalmodels
playedinthesediscoveries.Wealsosummarizepsychophysicalapproachestostudybittertastebothinanimal
modelsandinpediatricpopulations,andwecompareandcontrastbittertasteperceptionbetweenadultsand
childrenandidentifygapsinknowledge.Whenappropriate,wereferencereviewarticlestodirectthereadertothe
widerliterature.
3.OverviewofBitterTaste
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Tasteisoneofthesensesthroughwhichhumansandotheranimalsperceivetheirenvironment.Oneoftheprimary
tastequalitiesisbitter,asensationthatariseswhenspecificchemicalsaredetectedbyspecializedreceptorsinthe
tongue,aswellasotherpartsoftheoralcavity(e.g.,throat).Indevelopingeffectivestrategiesforreducingthebitter
tasteofmedications,itisimportanttoconsiderthebasicfunctionalarchitectureofthegustatorysystem(illustrated
schematicallyintheFigure).Wesummarizethestateofknowledgeaboutbittertaste,fromperipheralreceptorsto
thebrain,andlinkthissystemwithperception.
Figure
HowBitterWorks:theprocessofbitterperception.Thegenerationofbitter
tastestartswhenabittercompoundenterstheoralcavity,wheretheligand
bindstoaT2RGproteincoupledreceptorexpressedintheapical
membraneofreceptorcellsfound...
a.NeurobiologyofBitterTaste
Theprincipalsensoryorganofgustationisthetastebud,
acollectionofabout50100specializedepithelialcells,someofwhichservetheroleofreceptors.Receptor
proteinsareexpressedontheapicalmembranesofmicrovilli,whichprotrudeintoaporeintheepithelium,where
theyhaveaccesstotheoralenvironment(seesegmentlabeledTasteBudintheFigure).Thus,stimulimustbein
solutiontoadequatelyreachandstimulatethereceptorcells.
i.PeripheralandCentralAnatomyoftheGustatorySystem
Thetastebudsarebathedinexcretionsfromthesublingual,submaxillary,andparotidsalivaryglands,aswellas
fromnumerousminorsalivaryglandsthroughouttheoralepithelium.Althoughthereissufficientevidencethat
salivaplaysasignificantroleintastereceptoractivationbyorallyappliedchemicalcompounds,itscontributionhas
notbeenextensivelystudied.Prolinerichproteinsfoundinsalivacanbindwithbittertastingtanninsfoundinsome
foods,increasingtheiracceptability.28Prolinerichproteinsarisefromgeneclustersthatareinterleafedwithbitter
receptorgenes,hintingatacommonregulatorymechanismandfunction.29Abetterunderstandingofthefunction
ofsalivaintastereceptorprocessesmayhelpuscurtailthebitternessofmedicines.
Tastebudsaredistributedindistinctfieldsintheoralcavity(seeOralsegmentontheFigure).30,31Intheanterior
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tongue,tastebudsarehousedinspecializedprotrusionscalledfungiformpapillae.Intheposteriortongue,thetaste
budsarefoundinaseriesoftrenchlikestructuresinthelateralmargins,referredtoasthefoliatepapillae,andin
moatlikestructuresinthedorsalsurface,referredtoasthecircumvallatepapillae.Extralingualtastebudsarealso
foundonthesoftpalateandinthelaryngealepithelium.Eachfieldisselectivelyinnervatedbyaspecificbranchof
theseventh,ninth,ortenthcranialnerve,whichallprojecttotherostralnucleusofthesolitarytract(NTS)inthe
medulla,wheretheyterminateinaroughlyoverlappingorotopicfashion.3234
Interestingly,thepathwayofgustatorysignalsthroughthebrainvariessomewhatacrossthemammalianspecies
examined.35Forexample,inrodentsandlagomorphs(e.g.,rabbitsandpikas),tasteresponsiveneuronsinthe
NTS,inadditiontocontributingtolocalhindbraincircuitsinvolvedwithoromotorandautonomicfunction,3638
projecttotheparabrachialnucleus(PBN).TheprojectionsfromPBNneuronsbifurcate,withonesetterminatingin
ventralforebrainstructuresassociatedwithhomeostaticfunctionsandaffectiveprocesses,andtheotherinthe
parvocellularsubdivisionoftheventralposteriormedialnucleusofthethalamus,fromwhichneuronssendtheir
axonstoterminateintheinsularcortexsgustatoryzone.Inprimates,theprojectionsofthetasteneuronsofthe
NTSbypassthePBNandterminateinthethalamus,whosecellsprojectdirectlytotastecortex(seeFigure,
CentralNervousSystem).39Thus,theventralforebraininprimatesreceivesitstasteinputfromcortical
structures.Manyofthesepathwaysarereciprocal,settingthestageforsignificantfeedbacktomodulatethesignals.
Regardlessofthedifferentanatomicalpathsoftastesignalsthroughbraininvariousmammalianorders,the
significanceofwhichremainstobeunderstood,inallcasestastesignalscanbemodulatednotonlyintheperiphery
butalsoanywherealongthecentralgustatorypathway.Forexample,theadageaspoonfulofsugarhelpsthe
medicinegodownreceivessomesupportfromevidencethatsucrosecanindeeddecreasetheperceivedintensity
ofquinine,aphenomenonreferredtoasmixturesuppression.40,41Althoughsomemixturesuppressioneffects
likelyhaveaperipheralorigin,41,42therearecentralcontributionsaswell.40,41Forexample,ifthesucrosesolution
isappliedtoonesideofthetongueandthequininesolutiontotheother,theperceivedintensityofthequinineis
attenuateddespitethestimulationofindependentlingualreceptorfields.41Further,anestheticblockofthenerve
thatinnervatesthefrontofthetongueincreasesperceivedbitternessofquinineappliedtothebackofthetongue,
presumablypreventinginhibitionarisingfromanteriorlingualtastesignals.42
ii.TasteReceptorMechanismsandtheT2RFamily Therearetwogeneralclassesoftastereceptormechanisms:the
Gproteincoupledreceptors(GPCRs),involvedinmediatingsweet,bitter,andumamitaste,andtheionchannel
receptors,implicatedinsaltandsourtaste.4347Theactivitiesofsomeofthesereceptorsand/ortheirdownstream
transductionintermediariesarethermallysensitive,4850makingtemperatureacandidatestrategyformodulating
thetasteofmedicine.
Allofthesereceptorproteinsareexpressedinavarietyoftissuesinthebody.5155Forexample,theGPCRsthat
serveastastereceptorsarealsofoundinthegut.51,52,54Thishasledtothetermguttaste,whichismoreofa
metaphorthanareality:asdescribedbelow,tasteresultsnotfromthereceptorsthemselvesbutfromthe
downstreamneuralconsequencesoftheactivationofthesereceptors.Bitterreceptorsarealsoexpressedinthe
ciliatedcellsofthesinonasalepitheliumandcantriggerimmuneresponseswhenstimulatedwithchemicalsignals
frombacteria.56
TheGPCRssharecertaintransductionintermediariesintastereceptorcells,suchasgustducin,PLC2,and
TrpM5,whichultimatelyleadtoreleaseoftheneurotransmitter(seetheCellandMolecularsegmentintheFigure
).57Insomecells,theGproteinsubunitgustducinhelpsmediateresponsestobothbitterandsweettasting
ligands.58,59BecauseGPCRtransductionsignalingcomponentsaresharedbybothbitterandsweettasting
ligands,theymaynotbeselectivetargetsfordecreasingthebitternessofmedications.However,althoughtoour
knowledgeitisuntested,thedeactivationofthesesignalingcomponentsonatemporarybasiscouldproveuseful
becauseevenifsweetnessispotentiallyattenuated,thedecreaseinbitternesscouldleadtoanoverallincreaseinthe
acceptabilityofthemedicine.
TheT2Rfamilyoftastereceptorswasdiscoveredalittlemorethanadecadeago.60,61Itconsistsofabout25
GPCRsthatserveastheprincipalreceptorsformediatingbittertaste.Althoughmanyofthereceptorsremaintobe
deorphaned(i.e.,determinewhichligandsactivatethem),mostT2Rsstudiedhavebindingprofilesthatinvolve
severaldifferentbittertastingligands.62,63Likewise,agivenbittertastingligandcanactivatemorethanone
T2R.62,63Asmightbeexpected,therearesomegeneticvariantsinthereceptorswithinandacrossspecies.63For
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example,asubsetofthepopulation,classifiedasnontasters,cannotdetectthepresenceofthecompounds
propylthiouracil(PROP)andphenylthiocarbamide(PTC)atmoderateconcentrationsthatallothers,referredtoas
tasters,findexceptionallybitter.64Thenontasterphenotypeisduetoahaplotypeinvolvingpolymorphismsat
threeaminoacidpositionsinthehT2R38protein,whichisknowntobindwiththesecompounds.65Likewise,
geneticvariantswithinanotherclusterofbitterreceptorgenesaffecttheabilitytoperceivethebitternessof
quinine,66abitterchemicalusedinthepasttotreatmalaria.Thus,variationinthecomplianceofchildrentoingest
particularliquidmedicationscouldbeattributabletopotentialpolymorphismsintheseorotherT2Rsthathaveyet
toberevealed.
Developingresearchindicatesthatreceptorsforstimuligeneratingdifferenttastequalitiesarenotcoexpressedin
tastebudcells.44,45,47,60,67Thus,ifatastebudcellexpressestheT1R2+T1R3receptorresponsibleformediating
sweettaste,itwillnotexpressanyoftheT2Rsthatserveasthereceptorsforbittertastingligands.Althoughrodent
studiesfirstindicatedthatvirtuallyallT2Rswerecoexpressedontastereceptorcellsresponsivetobitter
ligands,60,61laterhumanstudiesrevealedthatmostT2RexpressingcellsexpressonlyasubsetoftheT2R
members.63Nevertheless,aconsistentsystematicpatterntothisexpressionhasnotbeenidentified.Thislackofco
expressionsetsthestagefortheflowoftasteinformationthatgivesrisetodifferentqualitativetasteperceptions,
althoughthereisplentyofopportunityforconvergenceinthetransmissionofthesignalsthroughthebrain.
iii.NeuralResponseProfilestoT2RLigands Inadditiontooverlapamongligandsforreceptorsandreceptorsfor
62,63
ligands,
thereisoverlappingexpressionoftheT2Rmembersinthesubsetoftastebudcellsresponsivetobitter
compounds.Surprisingly,however,imagingexperimentsofintracellularchangesincalciumconcentrationinrat
tastebudcellsinsituinresponsetobitterstimuliindicatemuchnarrowertuningproperties:ofthe374cellstested,
69respondedtoatleastoneofthefivebitterligandsinthetestpanel,andofthese,45cellsrespondedtoonlyone
and18respondedtoonlytwo.68
Becausesingleaxonsfromatastenervebranchareclosetothetongueandinnervatemorethanonetastecell,any
selectivitypresentintastereceptorcellscouldbelostbyearlyconvergenceinthesystem.Theextenttowhichthis
occursattheganglioncelllevelremainsunderstudied.Mostpriorstudiesusedonlyquininehydrochlorideasthe
bitterstimulus,ratherthanadiversesetofbitterligands.Moreover,thevastmajorityofperipheralandcentral
electrophysiologicalresultsintheliteraturearebasedonanteriortonguestimulation,reflectingthecontributionof
onlyabout15%ofthetotaltastebudpopulationandcircumventingthetastereceptorfieldoftheposteriortongue,
whichhasthedensestexpressionofT2Rs.60Thisisdue,inpart,tothedifficultyineffectivelyperfusingthefoliate
andcircumvallatetrenchesintheposteriortonguewithstimulussolutionsinananesthetizedpreparation.
Despitethesedifficulties,twostudiesstandoutinthisregard.Frank69publishedthefirstcomprehensivesetof
findingsdetailingtheresponsepropertiesofsinglefibersintheglossopharyngealnerve.Sheinsertedapipetteinto
thecircumvallatepapillaoftherat(rodenttongueshaveonlyonecircumvallatepapilla,vs.10inthehuman
tongue)andtestedsalts,acids,sugars,andquinine.Althoughinherpriorstudiesquinineresponsivesinglefibersin
thechordatympaninerveinnervatingthefrontofthetonguerespondedbesttoacidsandotherelectrolytes,70inthis
studyasetoffiberswasidentifiedthatrespondedselectivelytoquinineandnottotheotherstimuli.Thisindicatesa
segregationofquinineevokedsignalsfromthoseofothertastequalities,consistentwiththesocalledlabeledline
modelofneuralcoding,inwhichactivityinagivenclassofneuronsisnecessaryandsufficientforgeneratinga
specifictastequality.71
Intheotherstudy,Dahlandcolleagues72recordedsinglefiberresponsesinthechordatympaninerve(anterior
tongue)andtheglossopharyngealnerve(posteriortongue)toapanelofbittertastingligands.Notallligands
stimulatedthesamefibers,suggestingthatsignalsmaybepresentintheoverallperipheralinputthatpermitssome
discriminabilityamongtheseparticularbittercompounds.Thishasbeentakenasevidenceforanensembleor
acrossneuronmodelofneuralcoding.
Oncethesignalsfromtheperipheralnervesreachthebrain,thereisopportunityforfurtheranatomicalconvergence.
Fromafunctionalstandpoint,thepatternofthisconvergenceiskeyintermsofhowthenervoussystemrepresents
informationaboutchemicalcompoundscontactingtheoralepithelium.Indeed,thereisevidencethatthebreadthof
tuningoftasteresponsiveneuronsincreasesinthebrain.However,somenarrowlytunedneuronsarestillpresentin
thepopulation,anditisuncleartowhichtastefunctionagivenneuroncontributes.Thus,someneuronsmightbe
responsivetotheaffectivevalenceofthestimulus,whereasothersmightcodefortastequalityandcontributeto
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stimulusidentification.73
Theliteratureonresponsesofcentraltasteneuronstobittertastingstimuliinrodentmodelsismixed.Formany
yearsthebitterstimulusquininewasincludedinmanyelectrophysiologicalstudiesofneuronaltasteresponsesin
severalcentralgustatorystructures,butdespiteitspotentbehavioraleffects,neuronalresponseswereweakor
nonexistentpossiblybecausemanystudiesdidnotstimulatetheposteriortongue.Inrecentyears,however,some
morerobustresponsesofneuronsinthegustatoryzoneoftheNTSandPBNtoavarietyofbittertastingligands
havebeenrevealed.7476Indeed,aclassofneuronshasbeenidentifiedthatrespondbesttobittercompoundsand
littletocompoundsassociatedwithothertastequalities.74,75Withinthisclass,however,notallbittercompounds
areequallyeffectivestimuliforagivenneuron.Thismaybeduetoidiosyncraticupstreamconnectionsoriginating
fromthespecificT2Rsexpressedinthetastereceptorcells,oritmayrepresentafundamentaldistinctionin
organizinginputsfromsubclassesofbittertastingligands.Someoftheionicbittercompoundscanalsostimulate
neuronsthatrespondbesttoacidsandelectrolytes,addinganotherlayerofcomplexitytotheunravelingofthe
neuralrepresentationofbittertaste.74,75
Inasetofrecentresultsusingatwophotonimagingprotocoltomeasurecellularcalciumresponses,anatomically
distinctclustersofneuronswerefoundintheinsularcortexofthemousethatappearedtorespondselectivelyto
tastecompoundsassociatedwithspecificbasictastequalities,includingagroupthatrespondedonlytobitter
compounds.77Thedisparitybetweenthesefindingsandthelackofevidenceofexplicitchemotopyfrom
electrophysiologicalstudiesofcentralneuronaltasteresponses71hasyettoberesolved.However,resultsfroman
earlierstudyusingalessspatiallypreciseopticalimagingtechniqueprovidesupportforsomedegreeofaspatial
mappingoftastequalityinthiscorticalregion.78
Fromallthatwenowknowaboutbitterperceptionanditsmultiplereceptors,itisnotsurprisingthatthebittertaste
oforalpharmaceuticalsisanongoingformulationproblem.Themechanicsofbittertastesignalingsuggestthatit
shouldbeamenabletothemethodsofpharmacology.79However,thelargenumberofbittertastingcompoundsand
receptorsmakesblockingbitternessatthereceptorleveldifficultbecausemedicinesmayhavemultiplebitter
compoundsthatstimulatemultiplereceptors,andeachreceptormayrequireitsownantagonist.Asmentioned
above,theblockadeofsecondmessengersignalingposesproblemsbecauseseveralcomponentsofthebittertaste
transductionpathwayaresharedwiththosemediatingsweettaste,andattenuationbothbitternessandsweetness
mayposepracticalproblemsbecausesweetenersareacommonlyusedagentstoreduceperceivedbitterness.
Nonetheless,temporarynonselectiveblockadeofthesetastetransductionpathwayscouldleadtoanoverall
increaseintheacceptabilityofthemedicine.
b.LinkingtheNeurobiologyofBitterTastetoPerception
Thediscussionaboveprovidesacursorydescriptionofthehardwareofthegustatorysystem,withafocuson
neuralmechanismsunderlyingbittertaste.Mostofwhatwehavelearnedaboutthemolecularaspectsofbittertaste
transductionhasbeenfromexperimentalanimalmodels,mostlyrodents.
However,withoutdatadefiningthepsychophysicalpropertiesofvarioustastecompoundsandtheirmixtures,we
cannotlinktheunderlyingneurobiologywithperception.Inthisregard,animalmodelsareparticularlyuseful
becauseeffectsofveryselectivemanipulationsofthegustatorysystemcanbestudiedinahighlysystematicand
quantitativeway,inawidevarietyoftissues,includingthenervoussystem,aswellasintasterelatedbehavior.In
suchefforts,however,itisimportanttobemindfulofseveralinterpretiveguidelines.73
First,whenmostpeopletalkabouttaste,theyareactuallyreferringtoflavor.Flavorcanbeconsideredthe
perceptualintegrationofsignalsfromthegustatory,olfactory,andtrigeminalsystems.80Tothespecialist,however,
tastereferstothebehavioralandphysiologicalconsequencesofstimulatingtastereceptorcellsintheoralcavity.
Accordingly,thepotentialfortastestimulitoactivatenongustatorysensorysystems,includingthoseofa
visceroceptivenatureinthecaseswherethetastesolutionsareswallowed,mustbeconsidered.
Second,perceptioncannotbemeasureddirectlyitmustbeinferredfrombehavior.Theveracityofthatinference
dependsheavilyontheprocedureusedtomeasurethebehavior,whetherstudyinganimalsorhumans.
Third,tastefunctionismultidimensional.Thesensory/discriminativedimensionencompassesstimulus
identification,includingthebasictastequalitiessweetness,sourness,saltiness,bitterness,andumami.Theaffective
dimensioninvolvesthehedonicevaluationoftastestimuli,ultimatelypromotingordiscouragingingestion,whichis
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perhapsmostrelevanttoaddressingtheunpalatablenatureofbittermedicinesinchildren.Physiologicalreflexesare
alsotriggeredbytastestimuli,suchassalivationtriggeredbytheoralsamplingofalemon.Thus,behavioral
outcomesfromagivengustatorymanipulationneedtobeinterpretedinlightofthedomain(s)beingassessed.
Finally,aneuronsresponsetoanorallyappliedchemicalstimulusdoesnot,inandofitself,revealthefunctional
domain(s)towhichthecellcontributes.Inthissense,behavioralobservationsareindispensableinunderstandingof
theneurobiologicalmechanismsunderlyingtastefunction.
4.BehavioralAssaysinAnimalModels
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Althoughbehavioralproceduresinvolvingnonhumansubjectsaretimeconsumingandresourceintensive,their
valueisindisputablebecausetheylinktheneurobiologyofthegustatorysystemtobehaviorand,byinference,
perceptioninthesameanimalmodel.Rodentsareparticularlyusefulanimalmodelsforstudyingtasteperception:
theyarecommensalwithhumansandthushaveasimilarsenseoftaste.Animalmodelsalsoshareothersimilarities
withveryyoungchildren:forbothpopulations,behaviorratherthanlanguagecommunicatesimportantinformation
abouttheirsenseoftaste.Thebehavioraloutcomesfromanimalmodelscanthenbecomparedwithpsychophysical
resultsfromsimilarexperimentsconductedwithhumansubjects,providingapotentialbridgebetweentheanimal
neurobiologicaldataandhumantasteperception.
Themostcommonbehavioralprocedureforassessingtastefunctioninanimalmodels(andinyounginfants,as
describedbelow)remainsthetwobottlepreferencetestinwhichtheanimalissimultaneouslypresentedwithtwo
liquidstimuli(e.g.,sucrosesolutionvs.water)foraspecifiedduration.Althoughthesetestsprovideareasonable
firstapproximationofananimalstasteresponsivenesstoagivencompoundandhavethevirtueofsimplicity,their
interpretationislimitedbecauseintakeandchoicecanbeinfluencedbynongustatorycontributions,mostnotably,
thosearisingfrompostingestiveevents(e.g.,satietyornausea).Overthelastseveraldecades,however,avarietyof
behavioralprocedureshavebeendevelopedthatassesstastefunctionmoreselectively.81Theseprocedurescould
havegreatutilityintestingvariousstrategiesforscreeningdrugsintheirearlystagesofdevelopmentorfor
modulatingthebittertasteofadrugbasedonmorefundamentalphysiologicalormolecularresearch.Inthissection
webrieflysummarizeeachofthesemethodologiesinanimalmodels.
a.BriefAccessTest
Thebriefaccesstastetestisaneffectivewaytocircumventthelimitationsofintaketestsbypresentingsmall
volumesoftastesamplesandmeasuringimmediatebehavioralresponses.Generally,variousconcentrationsofa
giventastecompoundarepresentedinverybrieftrials,ontheorderofseconds,andlickingresponsesaremeasured
withthehelpofspecializedtestingdevices8290.Thisprocedureismostcommonlyusedtotestratsandmice.With
normallypreferredtastestimuli,suchassucrose,theanimalscanbetestedineitheranondeprivedorafood
deprivedstate,andamonotonicincreaseinlickingasafunctionofconcentrationisgenerallyobserved.With
aversivestimuli,suchasbittertastingligands,animalsaretestedinawaterdeprivedstate,andamonotonic
decreaseinlickingasafunctionofconcentrationgenerallyoccurs.
Theseresponsesaresensitivetogustatorymanipulations.Forexample,miceinwhichthegeneencodingtheGPCR
tastetransductionintermediariesPLC2andTRPM5havebeenknockedoutdisplayrelativelyflatconcentration
responsecurvestosweetandbitterstimulicomparedwithwildtypecontrols.57,91,92Interestingly,theknockout
micestilldisplaysomelickingavoidanceofveryhighconcentrationsofcertainbittertastingcompounds,suchas
quinineordenatonium,suggestinganalternativehighthresholdtastetransductionpathway(s)fortheseligandsthat
isindependentofPLC2andTRPM5.91,92Althoughthebriefaccesstestdoesnotassesstastequalityperception
perse(e.g.,NaCl,citricacid,andquinineallproducedecreasinglickingfunctions),itisaneffectivemeasureofan
animalsaffectiveresponsivenesstoatastestimulusandhasgreatpotentialutilityfortestingmaskingagentsand
otherstrategiestoattenuatetheaversivenessofmedicines.
b.TasteReactivity
Manyanimals,includingrodentsandhumans,displayreflexlikeoromotorresponsestotastestimuli,93whichhas
beentermedtastereactivity.9497Thishasbeenbeststudiedinratsinwhichtastesolutionsaredelivereddirectly
intotheoralcavitythroughsurgicallyimplantedcannulas.Normallypreferredtastestimuli,suchassugars,elicit
tongueandmouthmovementsdirectlyproportionaltotheconcentrationofthesolution.Thesearecollectively
referredtoasingestivebehaviors.Normallyavoidedtastestimuli,suchasquinine,elicitgapes,chinrubs,forelimb
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flails,andheadshakesdirectlyproportionaltotheconcentrationofthesolution,andallofthesearegenerally
accompaniedbyactivefluidejection.Thesearecollectivelyreferredtoasaversivebehaviors.Transectionofthe
glossopharyngealnerve,whichinnervatesthetastebudsoftheposteriortonguewhereT2Rsaredenselyexpressed,
virtuallyeliminatesthecharacteristicaversiveoromotorresponsestointraorallydeliveredhighlyconcentrated
quininesolutions,98100whichreturnwhenthenerveregenerates.100
Althoughbittertastestimuliareoftenaversive,notallaversivetastesarebitter.Accordingly,tastereactivitydoes
notassesstastequalitybutratherprovidesinformationabouttheacceptabilityofvarioustastestimuli.Nonetheless,
theseprocedurescouldcontributesignificantlytodevelopingwaystoincreasemedicationpalatability.
c.ConditionedTasteGeneralizationandDiscrimination
Theseprocedurescanmoreselectivelyassesstastequalityindependentoftheinherenthedoniccharacteristicsofthe
stimulus,byestablishingatastestimulusasaconditionedsignal.Forexample,withtheconditionedtasteaversion
procedure,commonlyusedinrodents,86,90,101,102theingestionofaspecifictastestimulusispairedwith
administrationofanagentthatproducestemporaryvisceralmalaise(presumablynausea).Onsubsequentoccasions,
theanimalwillavoidingestingtheconditionedstimulusandothersthathaveasimilarqualitativetaste,a
phenomenoncalledgeneralization.Whenthetestarrayincludessucrose,quinine,NaCl,andcitricacid,inferences
canbemadeabouthowsweet,bitter,salty,andsourtheconditionedstimulusis.Althoughintakecomparedwith
nonconditionedcontrolanimalsisoftentheprimarydependentmeasure,briefaccesstestsandtastereactivity
measurescanalsobeused.
Onelimitationoftheusethisparadigmtoassessqualitativecharacteristicsofnaturallyaversivetastestimuliisthat
theyarealreadyunconditionallyavoided.However,operantconditioningprocedurescancircumventthis
shortcoming.Intheseprocedures,asmallvolumeofatastecompoundservesasacueinthepresenceofwhicha
specificresponseisrewardedorpunished.Forexample,usingaspeciallydesignedgustometer,Grobeand
Spector103trainedonegroupofthirstyratstolickaspecificdrinkingspoutaftersamplingsucrose(thestandard
stimulus)andadifferentspoutaftersamplingquinine,citricacid,orNaCl(thecomparisonstimuli).Iftherats
respondedcorrectly,theywererewardedwithwaterifnot,theywerepunishedwithatimeout.Threeothergroups
weretrainedwithquinine,citricacid,andNaCl,respectively,asthestandardstimulusandtheremaining
compoundsasthecomparisonstimuli.Concentrationsofallstimuliwerevaried,renderingintensitycuesirrelevant.
Afterallfourgroupslearnedthetask,atestcompoundwasrandomlyinterjectedduringthetastetrials.By
observingwhichspouteachanimalwenttoaftersamplingtheteststimulus,theexperimenterswereabletoinfer
tastequalityofthesampleusingtheresponseprofilesacrossallfourgroups:sweetness(sucrosestandardgroup),
bitterness(quininestandardgroup),saltiness(NaClstandardgroup),andsourness(citricacidstandardgroup).
Asimilarprocedurecantesthowwellratsandmicecandiscriminatebetweentwospecificcompounds.Therehas
beensomedebateaboutwhetheranimalscandiscriminateamongbittertastingcompounds.Asnotedabove,theco
expressionofT2Rsintastereceptorcells,aswellastheirsomewhatbroadtuningprofiles,predictspoor
discriminability,whereasthecalciumresponsesoftastebudcellspredictgooddiscriminability.Theresponse
profilesforcentraltasteneuronscanbeusedtosupporteitherprediction.SpectorandKopka104testedwhetherrats
coulddiscriminatebetweenquinineanddenatonium,forwhichcalciumimagingsuggestedahighdegreeof
discriminability.Theprocedurewassimilartotheonedescribedabove:ratswererewardedforlickingonespout
whenquininewasdeliveredandforlickingtheotherwhendenatoniumwaspresentedincorrectresponseswere
punishedwithatimeout.Theseratscouldnotbetrained,butdidsubsequentlylearntodiscriminatequininefrom
KCl.
AsecondgroupofnaiveratswerefirsttrainedtodiscriminatequininefromKClthendenatoniumwassubstituted
forquinine,andperformanceremainedunperturbedontheveryfirstsession,suggestingthatdenatoniumand
quininesharesimilarqualitativeproperties.Toshowthatanystimulussubstitutiondoesnotnecessarilyresultin
unalteredperformance,SpectorandKopkasubstitutedNaClfordenatonium.Inthiscase,performancedroppedto
chancelevelsonthefirstsessionandthensubsequentlyimprovedacrosssessionsastheanimalslearnedthenew
discriminationtask.Finally,thesesamehighlytrainedratsweretestedonthequininevs.denatoniumtask,andtheir
performanceremainedatchanceover15testsessions.Accordingly,ifratscandiscriminatequininefrom
denatonium,itislikelyverydifficult,suggestingthatthetwocompoundsproduceaunitaryqualitativetaste
perceptionthatonecouldperhapscallbitterness.Whetherotherbittertastingligandscanbediscriminatedfromone
anotherremainstobetested.Onamoreconceptuallevel,failuretodiscriminateisalwaysmorecompellingthanis
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success,providedlearningandintensityeffectscanberuledout,becauseitsuggeststhatanidentityrelationexists
somewherealongthesensoryneuraxis.
5.BehavioralAssaysinChildren
Goto:
Amajorchallengeinformulatingpharmaceuticalsforchildrenspalatesistheidentificationofmethodstoassessthe
acceptanceofthetasteofthemedicines,oncetheyareapproved,andtodetermineinthelongtermwhichmethods
yielddatathatpredictadherence/compliancetomedicationregimes.105Whenconductingresearchinchildren,
severalmethodologicalissuesneedtobeaddressed.
First,youngchildrenaremorepronetoattentionlapsesandhaveshortermemoryspanscomparedwithadults.
Therefore,anymethodrelyingonsustainedattentionthatplacesdemandsonmemorycouldyieldspurious
findings.Second,becauseyoungchildrentendtoanswerquestionsintheaffirmative,aforcedchoice
categorizationprocedureisgenerallypreferred.Ageappropriatetasksembeddedinthecontextofagamethatare
funforchildrenandminimizetheimpactoflanguageandthestageofcognitivedevelopment,areparticularly
effective.Third,beforeactualtestingandafteraperiodofacclimation,theexperimentershouldascertainwhether
thechildcomprehendsthetask.Trainingtoolsareneededtodeterminewhetheragivenchildhastheabilitytodo
thetask.Reproducibilityofthemeasuresovertimeshouldbebuiltintothedesignofthestudy.Allofthesespecial
featuresmustbeconsideredwhendevelopingsensorymethodsforchildren.
Avarietyofpsychophysicalmethodologieshavebeenemployedtoassesstasteperceptionandpreference
throughoutinfancy,childhood,andadolescence.106Themethodchosendependsontheobjectiveofthestudy,as
wellastheage(and,inturn,cognitiveandlanguageabilities)oftheparticipantsunderstudy.Thesepsychophysical
studiesontasteprovidedatarelevanttotwoseparateaspectsofsensation:(1)thesensitivityofthesystemto
chemicalstimuliand(2)thehedonicvalence,orpleasantness,ofthesensation.107,108
Thecenturylonglegacyofexperimentalresearchintastehasrevealedthat,liketheothersenses(sounds,109
smells,110,111andirritants112),childrenliveindifferentsensoryworldsthandoadults.Theseagerelated
differencesareespeciallystrikingfortaste.Withinhoursafterbirth,infantshavebeenshowntoprefersweetand
umamitastes113115andtorejectbittertastingliquids,116althoughadultlikesensitivitytosaltdoesnotemerge
untiltheinfantisapproximatelyfourmonthsofage.117Theirdietarylikesanddislikesprovidefurtherevidenceof
theirstrongerlikingforfoodsandbeveragesthattastesweet,118salty,119and,insomecases,sour120andtheir
profounddislikeofallthattastesbitter.Childrensheightenedlikingforsweetsandsalts,relativetoadults,probably
reflectstheneedforenergyorminerals,respectively,duringperiodsofmaximalgrowth,sincemanyfoodsrichin
energy(e.g.,mothersmilk,fruits)tastesweet.Thus,itisnotsurprisingthatmanypediatricformulationstaste
sweet.
TheTableprovidesanoverviewofsomeofthepsychophysicaltoolsusedtostudybittertasteinchildren(formore
thoroughreviewthatincludestheotherbasictastes,seeForestellandMennella2013106).Forpreverbalchildren,
thetoolsoftenfocusonreflexlikeresponses(e.g.,orofacialresponses)orconsummatoryresponsesmanyofthe
experimentalparadigmsforthisagegrouparesimilartothoseusedinanimalmodelstudies,85,94,116,121123as
reviewedabove.Becausevirtuallyallofthesemeasurescanbeassociatedwithacceptanceorrejection,they
presumablyinvolveahedoniccomponent.Atleastforhumaninfants,sensitivityandhedonicsaredifficultto
distinguish.108Forolderchildren,thepsychophysicaltoolsaremorecomplex,butverylittleresearchhas
establishedatwhatagechildrencanreliablyperformthesetasks.
Table
Examplesoftypesofpsychophysicaltoolsusedtoassessbittertasteand
medicationpalatabilityinpediatricpopulations.
a.TasteReactivity
Someoftheearliestinvestigationsontasteininfantsinvolvedvideotapinginfantsandthencharacterizingtheir
oromotorreflexeswhentastestimuliwereplacedonthetongueorintheoralcavity.114126In1988,Osterand
Rosenstein115developedamethodfordescribingorofacialresponseswithEkmanandFriesens127anatomically
basedFacialActionCodingSystem(FACS),whichcandissectvirtuallyanyfacialexpressionintoitsconstituent
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actionunits(AUs).Videorecordsareoftenanalyzedinslowmotion97toquantifytheactualnumberofaffective
reactionsinfantsexpresstoatastestimulus,asameasureofvalenceandintensity.128Thismethodrequirestrained
individuals(preferablycertifiedinFACS)toanalyzethevideoimagesandestablishreliabilityacrossscores,125
whichcanbetimeconsumingandcostly.
b.BriefAccessTests:IntakeandSucklingMethods
Ingestiveandsucklingresponseshavebeenusedsuccessfullytostudyresponsepatternsasafunctionofindividual
andagerelateddifferencesintasteperception.Methodsincludedeliveringsmallquantitiesoftastesolutionsdirectly
tothetongueorprovidingbriefaccesstomultiplebottlesinsuccessionthatcontainvarioustasteordiluent
solutions.113,129132Insomecases,atransducerwasembeddedintothenippleofthebottletomeasurethe
patterningofsucklinginresponsetothetastant.133,134Inothercases,infantsaretestedonrepeateddaysfortheir
acceptanceofafood(e.g.,cereal)thatdiffersintastequality,125,128whichrequirescontrollingforanumberof
variables,includingtimeofdayandtimesincetheinfantwaslastfed,andensuringthatappropriatecontrolsare
builtintothestudydesign.Onecantheninferfromthisresearchthatinfantsdetectabittertastesolution(e.g.,urea
solutions),andrejectitmorethanthediluent,iftheyconsumeless(orsuckless)ofthebittertastesolutionthanof
thediluentsolution.130,132
c.ForcedChoiceTrackingProcedure/Thresholds
Variousmethodshavebeenusedtomeasurehowsensitiveachildistoaparticulartastant(e.g.,tastethresholds)
andwhetherthereareindividualdifferences.Perhapsthemostwidelystudiedtastetraitrelatestothegenetically
determinedabilitytotastecompoundscontaininganNC=S(thio)group,suchasphenylthiocarbamide(PTC)and
itschemicalrelativepropylthiouracil(PROP),inhumanpopulations.1014Asmentionedabove,thesechemicals
tastebittertotasters,whereasnontasterseithercannottastethemorrequirehighconcentrationstorecognize
theirpresence.
AvarietyofmethodshavebeenusedtoassesssensitivitytoPROPand/orPTC.135138Often,theseinclude
forcedchoiceproceduresembeddedinthecontextofagame.BasedontheproceduresofAnlikerandcolleagues
(1991),139childrenwerepresented,insuccession,withsamplesofwaterandthenthreeincreasingconcentrations
ofPROP(56,180,and560M)andwereaskedtotastethesamplewithoutswallowing.137,140,141Ifthesolution
tastedlikewaterornothing,thentheywereaskedtogivethesampletoBigBird,apopulartelevision
character.Ifthesampletastedbad,yucky,orbitter,childrenwereaskedtogiveittoOscartheGrouchsohe
couldthrowitinhistrashcan.Childrenweregroupedbytheconcentrationofthefirstsample,ifany,thatwas
giventoOscartheGrouch.ChildrenwhowereheterozygousattheTASR38genelocusthatis,hadonetaster
andonenontasteralleleweremoresensitivetothetasteofPROPthanwereheterozygousadults.The
thresholdsofheterozygousadolescentswereintermediate,140andhomozygouschildrenandadultsshowedno
differenceinthreshold.
Inotherstudies,childrenwerepresentedwithaseriesofpairsofsolutions:waterpairedwithanaqueoustastant
(i.e.,pairedcomparisons).Insomecasestheaqueoustastantsincreasedinconcentrationwitheachpairpresented,
andthechildwasaskedtoindicatewhichsampleofthepaircontainedthetastantortastedstronger.Thelowest
concentrationsuccessfullydetectedinoneortwoconsecutivetrialswasrecordedasthedetectionthreshold.142
d.ScalingProcedures
Varioustypesofscalingmethods(i.e.,methodsinwhichsensationstovaryingconcentrationsofsuprathreshold
stimuliarequantified)havebeenusedtodeterminechildrenspreferencesandsensitivitytotastes.Dependingon
age,childrenarepresentedwithalineorothertypeofscalethatcontainspictorialorverbaldescriptorsinagraded
order.Althoughtherehasbeennosystematicdeterminationofwhatscalingtestismostappropriateforchildrenat
whatage,someresearchershaveconcludedthatuseofscalesinchildrenyoungerthanage5canbeproblematic
becausetheyhavenotmasteredtheabilitytorankthingsinorderofmagnitude.143
Avarietyofmethods,includingspontaneousverbalreportsfollowingdosing,timerequiredformedicationintake,
10cmvisualanalogscales,andhedonicfacescales,areusedbypharmaceuticalcompanies,marketingresearch
firms,andotherinvestigatorswhentestingchildren.144Severaldifferent5pointhedonicscaleshavebeen
developedtoassesstasteacceptabilityofpharmaceuticals.145149Thesescalestypicallyconsistoffivedifferent
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facialexpressionsaccompaniedbywrittenlabelsandareusedtoevaluatechildrenshedonicresponsesaftertasting
onemedicationatatime.DaviesandTuleu150searchedPubMedtoidentify30papersassessingmedication
palatabilityinchildrendatingbackto1984andfoundthathalfofthestudiesusedahedonicscaletorate
palatabilityandthatparticipantsincludedchildrenasyoungas3years.Although5pointscalestypicallywere
used,149scalesrangedfrom2points151to10points.152Theuseofsuchscalesinyoungchildrenispotentially
problematic,asitisnotclearatwhatagechildrenbegintousetheentirescaleversusjustthetwoextremes.105To
date,onlyafewstudieshaveexaminedthevalidityandreliabilityofhedonicscalesinyoungchildren.Wehighlight
someofthesestudiesandhowtheirfindingsprovideinsightintowhethersuchmethodsareevenvalidforpediatric
populations.
Sjovallandcolleagues153comparedspontaneousverbaljudgmentsanda5pointfacialhedonicscaleinchildren
givenfivedifferentpenicillinformulations.Althoughbothmethodssuccessfullydiscriminatedbetweenpediatric
formulationswhenusedwitholderchildren,forchildren6yearsandyoungerspontaneousverbalassessment
discriminatedbetweenformulationsbetterthandidthefacialhedonicscale.
Leonandcolleagues154examinedthereliabilityandvalidityoffacialhedonicscalesinchildrenwhoseagesranged
from4to10years.Childreninthestudytastedbiscuitscoveredwithdifferentflavorsofjam.Children4and5
yearsoldratedthejamsusinga2pointhedonicfacescale(likevs.dislike),whereasolderchildrenratedthem
usinga4pointhedonicfacescale(likeverymuch,like,dislike,dislikeverymuch).Forchildrenyoungerthan5
years,intersessionrepeatabilityofresultswiththehedonicscalewaspoor(Kendallcorrelation=0.18)anddidnot
correlatewithothermeasuresofpreferenceinthesamechildren.Incontrast,childrenolderthan5yearscould
reliablyusethe4pointhedonicscale,andresultscorrelatedwithothermeasuresofpreference.Thesestudies
illustratethedifficultyofusinghedonicscalesinyoungchildren.
e.ApplicationofMethodstoStudyBitterTasteinChildren
Somechildrenrefusetotakebittermedicines,whereasotherscomplyreadily.2Likewise,noteverychild(oradult)
isequallysensitivetothetasteofbittercompounds.137Manychildrenaremoresensitivetobittertastesthanare
adults.131,137However,becauseofthepaucityofresearchontheontogenyofbittertastesensitivity,wedonot
knowthefullextentofthedifferencesinperceptionbetweenadultsandchildrenandhowthatrelatestoindividual
genotype.Wehypothesizethatthesubstantialdegreeofsequencediversityandvariationthatexistintastereceptor
genes155mayunderlieindividualdifferencesinmedicationadherenceinchildrenrelatedtotaste.Althoughthese
individualdifferencesariseforavarietyofreasons(e.g.,temperament,156experience,157ethnicity/race158),the
bestknownexampleispersontopersongeneticvariation.Asdescribedabove,variationsinperceptionofthebitter
compoundPROParedueinlargeparttotasterandnontasterallelesofaparticularbitterreceptor.65,159Allele
frequenciesforthisgenediffermarkedlybyraceforexample,highsensitivitytothebitternessofPROPandrelated
compoundsismorecommoninAfricanpopulations.155
Arecentstudyexploredtherelationshipbetweengenotypeofoneofthe25bitterreceptorgenes(TAS2R38)and
medicationhistory.160Childrenyoungerthan10yearswhohadatleastonetaster(P)allele(PPorAPgenotype)
weremorelikelytohavetakenmedicineinsolidformulationthanwerenontaster(AAgenotype)children.We
hypothesizedthattheresistancetotakingbitterliquidformulationsmayrelatetocomplianceandthatbittersensitive
childrenmayberesistanttotakingbitterliquidformulationsandmotivatedtotrymedicineinpillformasan
alternative.Althoughchildrenweregenotypedforonlyoneofthe25knownbitterreceptors,allelesofthis
particularreceptormaybeaproxyforgeneraltasteability,138orbitterreceptorgenesmayoccurintightlylinked
clusters60suchthatgeneticvariationinthisreceptormayrelatetovariationinotherreceptors.Thisparticular
receptormayalsorespondmorebroadlythanpreviouslyunderstooddrugscommonlyusedinchildrens
medicationshavenotbeenwidelytestedinassaysdesignedtounderstandsuchreceptorligandinteractions.Further
studyoftherelationshipbetweenTAS2R38genotypeandliquidformulationintakeandcomplianceiswarranted.
Recentresearchhasrevealedthatcellbasedassaysareimperfectproxiesofthehumantasteresponse.Forexample,
TAS2R38hasthreevariantsitesthatgiverisetoseveraltasterandnontasterhaplotypes.Whencellbasedassays159
ofthesehaplotypesarecomparedwithstudiesofpeoplewiththosesamehaplotypes,141thereisagreementinmany
casesbutnotinall,especiallyforvariantsthatmaydirectlycouplewiththeGprotein.Thisstudyhighlightsthe
needforpsychophysicalaswellascellbasedmethodstounderstandthegenotypephenotyperelationshipfortaste
receptors.141
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Researchtofurthercharacterizehowtastereceptorgenotypeandotheraspectsoftastephenotypesrelateto
pediatricmedicationformulationandcomplianceisnecessarytohelpusdevelopbettermedicinesforpediatric
populations.Suchresearchcouldbeincorporatedintopediatricclinicaltrials,tohelpunderstandindividual
complianceduringthetrialandtoexpandourunderstandingoftheroleoftastegeneticsinbehavioralchoices.
Becausechildrenaremorebittersensitivethanareadults,andagerelatedchangesinbitterperceptionaremore
commonforpeoplewithparticulargenotypes,weneedtostudybothadultsandchildrenandtakegeneticvariation
intoaccountwheninterpretingtheresults.160Althoughwehavestudiedonlyafewexamplesofhowbitter
receptorgenotypecanaffectbitterperception,66,159,161164genotype,likeage,itisanimportantdeterminantof
perceptionandshouldbeconsideredinallmethodstoevaluatethetasteofmedicineandcompliance.
Manyinvestigatorsaredevelopinganewgenerationofmoleculestoinhibitbitterness.79However,therearevery
fewpeerreviewedstudiesontheireffectivenessinadults(reviewedinRoy1997165),andtoourknowledge,only
onestudy,conductedinourlaboratory,hasexaminedchildren.166Nevertheless,becauseoftheagerelated
differencesinbittertasteperception,wesuggestthatresearchaimedatreducingthebitternessofmedicine,suchas
evaluatingtheeffectivenessofbitterblockers,shoulddirectlyinvolvechildrenratherthanextrapolatingfromdata
collectedfromadults.
6.ArtificialSensorSystems
Goto:
Thereismuchdebateintheliteratureonwhetherartificialsensorscanbesuccessfulsubstitutesforthehuman
palateandreplacetheuseofsensorypanelists,sinceuseofthelatterisproblematicinindustryduetothepotential
toxicityofdrugsandsubjectivityoftastepanelists,problemsinrecruitingtastepanelists,motivationandpanel
maintenancewhenworkingwithunpleasantproducts.167Furthermore,becauseFDAunapproveddrugs
cannotbetastetested,useofartificialsensors,ithasbeenargued,canprovideimportantdataregardingthetasteof
thesedrugs.167,168
Theseartificialsensorydevicestypicallyarearraysofsensors,calledelectronicnosesforarraysofgassensors
andelectronictonguesforarraysofliquidsensors.Oftenthesedevicesaredesignedtoanalyzethelevelsof
variousingredientscomposingafluidmixtureandinavarietyofapplicationsinvolvingproductqualitycontrol.169
Butinrecentyears,thesedeviceshavebeenusedasananalyticalgustatorytoolinevaluating
pharmaceuticals.167,170173Ithasbeenarguedthatthisapproach,whoseadvantagesincludeitsspeed,relatively
lowcost,andlackofrisk,willhelpdevelopmorepalatablepediatricformulations.174177
Nevertheless,whethersuchartificialsensorysystemswillleadtosignificantinsightsthatwilladdresstheheartof
theprobleminpracticeremainstobeseen.Giventhenumerousandvariedcomponentsofperipheralandcentral
mechanismsinvolvedinthemediationofbittertaste(summarizedintheFigure),theabilityofanartificialsensorto
modelandpredictthepropertiesofthiscomplexbiologicalsystemisquestionable.Thus,theutilityoftheelectronic
tonguetooffermeaningfulguidanceinthedevelopmentofstrategiestoincreasethepalatabilityofpediatric
formulationsislikelytobelimitedtosimplyprovidingadetailedanalysisofthechemicalconstituentsinthe
mixture.However,itisquitepossiblethat,sincethisisanactiveareaofresearch,thesedevicesmightbemore
usefulinthefuture.
8.Conclusions
Goto:
Likeothersensorysystems,tasteisexperiencedthroughasensorywindowthatchangeswithageandexperience
andispartiallydefinedbygenetics.Childrenhavewelldevelopedsensorysystemsfordetectingtastes,aswellas
smellsandchemicalirritants,andtheirrejectionofunpalatablemedicationsreflectstheirbasicbiological
preferencesforsweet,salty,and,tosomeextent,sourtastesandrejectionofbittertastes.Sugars,salt,acids,and
othersubstanceshelpreducetheperceivedbitternessofseveralpharmaceuticals.Althoughaddingpleasantflavor
volatilessuchasbubblegummayalsohelpinducechildrentoconsumeamedicine,suchvolatilecompoundsare
oftennotveryeffectiveinsuppressingthestrongbittertastesassociatedwithmanymedications.
Thisaversiontobittercreatesaroadblockfororalformulationsundesirablechemosensorycharacteristicscan
hindertheacceptanceandusefulnessofmanybeneficial,safe,andefficaciousdrugs.Theunpleasanttasteofa
medicineisoftenasensoryexpressionofitspharmacologicalactivityinmanycases,themorepotentthedrug,the
morebitteritwillbe.178Themorebitter,themorelikelythedrugwillberejected.Bettertastingmedicationsmay
goalongwaytowardenhancingtheabilityofpediatricpatientstoadheretodrugtherapy,especiallywhenfailure
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toconsumemaydoharmand,insomecases,belifethreatening.179Thus,aprimarychallengeistoreducethe
bitternessandotheroffflavorsofpediatricformulations.
Adultpanelistswhoaresensitivetothepediatricpalate,newtechniquesinvolvinganimalmodels,andeven
electronicdetectiondevicesareamongthetoolsthatcanhelpevaluatethepalatabilityofmedicationsandpredict
complianceamongpediatricpopulations.Furtherdevelopmentofandconsensusregardingwhichpsychophysical
toolsarevalidandappropriateforusewithchildrenwillprovideabetterunderstandingofthesensoryworldofthe
child.Testingmultiplestrategieswillhelpusrefinemethodsthatmaybeusedtoassessacceptanceand
compliance/adherencebypediatricpopulationsofvaryingages,whichwillallowforcomparisonsacrossstudies.
Thesemethodsthencanbeappliedtoclinicaltrialstoobtaindatathatcanhelppredictinitialacceptanceversus
longtermcomplianceofamedication,andhowmedicationusageanddiseasestatemodifybittertasteperceptionof
thedruginchildren.Whilemuchoftheresearchwillbynecessityfocusontastetestingwithoutswallowing,there
arealsobitterreceptorsinthebackofthethroat180thatmaybeengagedprimarilyduringswallowingoftheliquid
medication.Theeffectofthesereceptorsontasteacceptancecanbestudiedduringclinicaltrialsinwhichchildren
notonlytastebutalsoswallowmedicine.
Whileprogresshasbeenmadeinourcurrentunderstandingofbittertaste,itisfarfromcomplete,andnewwaysto
reducethebitternessofcertainmedicationsmayyetbediscovered.Mostofourknowledgeontheneurobiological
mechanismsoftastehasbeenderivedfromanimalmodelsinwhichthegustatorysystemcanbeinvasively
manipulatedandstudied.Asdiscussedintheprecedingpages,avarietyofbehavioraltechniquescanbeusedto
linktasteperceptiontoitsunderlyingneurobiologicalprocesses.Accordingly,thesemodelsystemscanbeexploited
toevaluatepotentialstrategiestosafelyandeffectivelyattenuatebitterness.Suchanapproach,coupledwith
psychophysicalassessmentoftastefunctioninchildren,andultimatelyclinicaltesting,shouldincreasethechances
offindingsolutionstowhathasbeenthevexingproblemofbittertastereducingdrugacceptanceandcompliancein
pediatricpopulationsunderstandingbitternessbettermaytaketheguessworkoutofimprovingformulations.
ACKNOWLEDGMENT
Goto:
WeacknowledgethevaluablediscussionswithDr.GeorgeGiacoiafromtheEuniceKennedyShriverNational
InstituteofChildHealthandHumanDevelopment,NIH,DHHS,aswellasothermembersoftheTasteWorking
Group.JohanLundstrmprovidedguidanceabouthumantastebrainareas.
CONFLICTOFINTERESTSTATEMENT
PreparationofthisarticlewassupportedinpartbyNIHgrantsR01DC01187(JM),P30DC011735(DR),andthe
WashingtonDentalServiceEndowedProfessorship(SC).Fundingsourceshadnoroleinthestudydesigninthe
collection,analysis,orinterpretationofdatainthewritingofthemanuscriptorinthedecisiontosubmitthe
manuscriptforpublication.
Footnotes
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Publisher'sDisclaimer:ThisisaPDFfileofanuneditedmanuscriptthathasbeenacceptedforpublication.Asaserviceto
ourcustomersweareprovidingthisearlyversionofthemanuscript.Themanuscriptwillundergocopyediting,typesetting,and
reviewoftheresultingproofbeforeitispublishedinitsfinalcitableform.Pleasenotethatduringtheproductionprocesserrors
maybediscoveredwhichcouldaffectthecontent,andalllegaldisclaimersthatapplytothejournalpertain.
DEDICATION
WededicatethisreviewarticletothememoryofDr.BarryDavis,pastdirectorofthetasteandsmellprogramwithinthe
NationalInstituteonDeafnessandOtherCommunicationDisorders,andafriendandmentor.
ContributorInformation
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JulieA.Mennella,MonellChemicalSensesCenter.
AlanC.Spector,FloridaStateUniversity.
DanielleR.Reed,MonellChemicalSensesCenter.
SusanE.Coldwell,UniversityofWashington.
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