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GanongsReviewofMedicalPhysiology,25e>

Chapter8:SomatosensoryNeurotransmission:
Touch,Pain,&Temperature
OBJECTIVES
Afterstudyingthischapter,youshouldbeableto:
Namethetypesoftouchandpressurereceptorsfoundintheskin.
Describethereceptorsthatmediatethesensationsofpainandtemperature.
Definegeneratorpotential.
Explainthebasicelementsofsensorycoding.
Explainthedifferencesbetweenpainandnociception,firstandsecondpain,acuteandchronicpain,
hyperalgesia,andallodynia.
Describeandexplainvisceralandreferredpain.
Comparethepathwaythatmediatessensoryinputfromtouch,proprioceptive,andvibratorysensesto
thatmediatinginformationfromnociceptorsandthermoreceptors.
Describeprocessesinvolvedinmodulationoftransmissioninpainpathways.
Listsomedrugsthathavebeenusedforreliefofpainandgivetherationalefortheiruseandtheir
clinicaleffectiveness.

INTRODUCTION
Welearninelementaryschoolthattherearefivesenses(touch,sight,hearing,smell,andtaste)butthis
dictumtakesintoaccountonlythosesensesthatreachourconsciousness.Therearemanysensoryreceptors
thatrelayinformationabouttheinternalandexternalenvironmenttothecentralnervoussystem(CNS)butdo
notreachconsciousness.Forexample,themusclespindlesprovideinformationaboutmusclelength,andother
receptorsprovideinformationaboutarterialbloodpressure,thelevelsofoxygenandcarbondioxideinthe
blood,andthepHofthecerebrospinalfluid.ThelistofsensorymodalitieslistedinTable81isoverly
simplified.Therodsandcones,forexample,respondmaximallytolightofdifferentwavelengths,andthree
typesofconesarepresent,oneforeachofthethreeprimarycolors.Therearefivemodalitiesoftaste:sweet,
salt,sour,bitter,andumami.Soundsofdifferentpitchesareheardprimarilybecausedifferentgroupsofhair
cellsinthecochleaareactivatedmaximallybysoundwavesofdifferentfrequencies.
TABLE81Principlesensorymodalities.
Sensory
Modality
Stimulus
ReceptorClass
System
Tap,flutter540 Cutaneous
Somatosensory Touch
Hz
mechanoreceptor
Cutaneous
Somatosensory Touch
Motion
mechanoreceptor

ReceptorCellTypes
Meissnercorpuscles
Hairfolliclereceptors
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Deeppressure, Cutaneous
vibration60300 mechanoreceptor
Hz
Cutaneous
Somatosensory Touch
Touch,pressure
mechanoreceptor
Sustained
Cutaneous
Somatosensory Touch
pressure
mechanoreceptor
Somatosensory Proprioception Stretch
Mechanoreceptor
Somatosensory Proprioception Tension
Mechanoreceptor
Somatosensory Temperature Thermal
Thermoreceptor
Chemical,
Chemoreceptor,
Somatosensory Pain
thermal,and
thermoreceptor,and
mechanical
mechanoreceptor
Somatosensory Itch
Chemical
Chemoreceptor
Visual
Vision
Light
Photoreceptor
Auditory
Hearing
Sound
Mechanoreceptor
Angular
Vestibular
Balance
Mechanoreceptor
acceleration
Linear
Vestibular
Balance
acceleration,
Mechanoreceptor
gravity
Olfactory
Smell
Chemical
Chemoreceptor
Gustatory
Taste
Chemical
Chemoreceptor
Somatosensory Touch

Paciniancorpuscles

Merkelcells
Ruffinicorpuscles
Musclespindles
Golgitendonorgan
Coldandwarmreceptors
Polymodalreceptorsorchemical,
thermal,andmechanical
nociceptors
Chemicalnociceptor
Rods,cones
Haircells(cochlea)
Haircells(semicircularcanals)
Haircells(otolithorgans)
Olfactorysensoryneuron
Tastebuds

Sensoryreceptorscanbethoughtofastransducersthatconvertvariousformsofenergyintheenvironment
intoactionpotentialsinsensoryneurons.Thecutaneousreceptorsfortouchandpressureare
mechanoreceptors.Proprioceptorsarelocatedinmuscles,tendons,andjointsandrelayinformationabout
musclelengthandtension.Thermoreceptorsdetectthesensationsofwarmthandcold.Potentiallyharmful
stimulisuchaspain,extremeheat,andextremecoldaremediatedbynociceptors.Thetermchemoreceptor
referstoreceptorsstimulatedbyachangeinthechemicalcompositionoftheenvironmentinwhichtheyare
located.Theseincludereceptorsfortasteandsmellaswellasvisceralreceptorssuchasthosesensitiveto
changesintheplasmalevelofO2,pH,andosmolality.Photoreceptorsarethoseintherodsandconesinthe
retinathatrespondtolight.
Thischapterdescribesprimarilythecharacteristicsofcutaneousreceptorsthatmediatethesensationsoftouch,
pressure,pain,andtemperaturethewaytheygenerateimpulsesinafferentneuronsandthecentralpathways
thatmediateormodulateinformationfromthesereceptors.Sincepainisoneofthemainreasonsanindividual
seekstheadviceofaclinician,thistopicgetsconsiderableattentioninthischapter.Receptorsinvolvedinthe
somatosensorymodalityofproprioceptionaredescribedinChapter12astheyplaykeyrolesinthecontrolof
balance,posture,andlimbmovement.

SENSERECEPTORS&SENSEORGANS
CUTANEOUSMECHANORECEPTORS
Sensoryreceptorscanbespecializeddendriticendingsofafferentnervefibers,andtheyareoftenassociated
withnonneuralcellsthatsurroundthemformingasenseorgan.Touchandpressurearesensedbyfourtypes
ofmechanoreceptors(Figure81).Meissnercorpusclesaredendritesencapsulatedinconnectivetissueand
respondtochangesintextureandslowvibrations.Merkelcellsareexpandeddendriticendings,andthey
respondtosustainedpressureandtouch.Ruffinicorpusclesareenlargeddendriticendingswithelongated
capsules,andtheyrespondtosustainedpressure.Paciniancorpusclesconsistofunmyelinateddendritic
endingsofasensorynervefiber,2mindiameter,encapsulatedbyconcentriclamellaeofconnectivetissue
thatgivetheorgantheappearanceofacocktailonion.Thesereceptorsrespondtodeeppressureandfast
vibration.ThesensorynervesfromthesemechanoreceptorsarelargemyelinatedAandAfiberswhose
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conductionvelocitiesrangefrom~70120to~4075m/s,respectively.
FIGURE81

Sensorysystemsencodefourelementaryattributesofstimuli:modality,location(receptivefield),
intensity,andduration(timing).A)Thehumanhandhasfourtypesofmechanoreceptorstheircombined
activationproducesthesensationofcontactwithanobject.SelectiveactivationofMerkelcellsandRuffini
endingscausessensationofsteadypressureselectiveactivationofMeissnerandPaciniancorpusclescauses
tinglingandvibratorysensation.B)Locationofastimulusisencodedbyspatialdistributionofthepopulation
ofreceptorsactivated.Areceptorfiresonlywhentheskinclosetoitssensoryterminalsistouched.These
receptivefieldsofmechanoreceptors(shownasredareasonfingertips)differinsizeandresponsetotouch.
MerkelcellsandMeissnercorpusclesprovidethemostpreciselocalizationastheyhavethesmallestreceptive
fieldsandaremostsensitivetopressureappliedbyasmallprobe.C)Stimulusintensityissignaledbyfiring
ratesofindividualreceptorsdurationofstimulusissignaledbytimecourseoffiring.Thespiketrainsindicate
actionpotentialselicitedbypressurefromasmallprobeatthecenterofeachreceptivefield.Meissnerand
Paciniancorpusclesadaptrapidly,theothersadaptslowly.(ReproducedwithpermissionfromKandelER,
SchwartzJH,JessellTM[editors]:PrinciplesofNeuralScience,4thed.NewYork,NY:McGrawHill2000.)

NOCICEPTORS
Somecutaneoussensoryreceptorsarenotspecializedorgansbutrathertheyarefreenerveendings.Painand
temperaturesensationsarisefromunmyelinateddendritesofsensoryneuronslocatedthroughouttheglabrous
andhairyskinaswellasdeeptissue.Nociceptorscanbeseparatedintoseveraltypes.Mechanicalnociceptors
respondtostrongpressure(eg,fromasharpobject).Thermalnociceptorsareactivatedbyskintemperatures
above42Corbyseverecold.Chemicallysensitivenociceptorsrespondtovariouschemicalssuchas
bradykinin,histamine,highacidity,andenvironmentalirritants.Polymodalnociceptorsrespondto
combinationsofthesestimuli.
Impulsesfromnociceptorsaretransmittedviatwofibertypes,thinlymyelinatedAfibers(25min
diameter)thatconductatratesof~1235m/sandunmyelinatedCfibers(0.41.2mindiameter)thatconduct
atlowratesof~0.52m/s.ActivationofAfibers,whichreleaseglutamate,isresponsibleforfirstpain(also
calledfastpainorepicriticpain),whichisarapidresponseandmediatesthediscriminativeaspectofpainor
theabilitytolocalizethesiteandintensityofthenoxiousstimulus.ActivationofCfibers,whichreleasea
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combinationofglutamateandsubstanceP,isresponsibleforthedelayedsecondpain(alsocalledslowpain
orprotopathicpain),whichisthedull,intense,diffuse,andunpleasantfeelingassociatedwithanoxious
stimulus.Itchandticklearealsorelatedtopainsensation(seeClinicalBox81).
Thereareavarietyofreceptorslocatedontheendingsofnociceptivesensorynervesthatrespondtonoxious
thermal,mechanical,orchemicalstimuli(Figure82).Manyofthesearepartofafamilyofnonselective
cationchannelscalledtransientreceptorpotential(TRP)channels.ThisincludesTRPV1receptors(theV
referstoagroupofchemicalscalledvanilloids)thatareactivatedbyintenseheat,acids,andchemicalssuchas
capsaicin(theactiveprincipleofhotpeppersandanexampleofavanilloid).TRPV1receptorscanalsobe
activatedindirectlybyinitialactivationofTRPV3receptorsinkeratinocytesintheskin.Noxiousmechanical,
cold,andchemicalstimulimayactivateTRPA1receptors(A,forankyrin)onsensorynerveterminals.
Sensorynerveendingsalsohaveacidsensingionchannel(ASIC)receptorsthatareactivatedbypH
changeswithinaphysiologicrangeandmaybethedominantreceptorsmediatingacidinducedpain.In
additiontodirectactivationofreceptorsonnerveendings,somenociceptivestimulireleaseintermediate
moleculesthatthenactivatereceptorsonthenerveending.Forexample,nociceptivemechanicalstimulicause
thereleaseofadenosinetriphosphate(ATP)thatactsonpurinergicreceptors(eg,P2X,anionotropic
receptor,andP2Y,aGproteincoupledreceptor).TyrosinereceptorkinaseA(TrkA)isactivatedbynerve
growthfactor(NGF)thatisreleasedasaresultoftissuedamage.
FIGURE82

Receptorsonnociceptiveunmyelinatednerveterminalsintheskin.Nociceptivestimuli(eg,heat)can
activatesomereceptorsdirectlyduetotransductionofthestimulusenergybyreceptors(eg,transientreceptor
potential(TRP)channelTRPV1)orindirectlybyactivationofTRPchannelsonkeratinocytes(eg,TRPV3).
Nociceptors(eg,mechanoreceptors)canalsobeactivatedbythereleaseofintermediatemolecules(eg,ATP).
ASIC,acidsensitiveionchannelP2X,ionotropicpurinoceptorP2Y,Gproteincoupledpurinergicreceptor.

CLINICALBOX81Itch&Tickle
Itching(pruritus)isnotamajorproblemforhealthyindividuals,butsevereitchingthatisdifficulttotreat
occursindiseasessuchaschronickidneydisease,someformsofliverdisease,atopicdermatitis,andHIV
infection.Especiallyinareaswheremanyfreeendingsofunmyelinatednervefibersoccur,itchspotscanbe
identifiedontheskinbycarefulmapping.Inaddition,itchspecificfibershavebeendemonstratedinthe
ventrolateralspinothalamictract.Thisandotherevidenceimplicatetheexistenceofanitchspecificpath.
Relativelymildstimulation,especiallyifproducedbysomethingthatmovesacrosstheskin,producesitchand
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tickle.Itisinterestingthataticklingsensationisusuallyregardedaspleasurable,whereasitchingisannoying
andpainisunpleasant.Itchingcanbeproducednotonlybyrepeatedlocalmechanicalstimulationoftheskin
butalsobyavarietyofchemicalagents,includinghistamineandkininssuchasbradykinin,thatarereleased
intheskininresponsetotissuedamage.KininsexerttheireffectsbyactivationoftwotypesofGprotein
coupledreceptors,B1andB2.ActivationofbradykininB2receptorsisadownstreameventinprotease
activatedreceptor2(PAR2)activation,whichinducesbothanociceptiveandapruritogenicresponse.
THERAPEUTICHIGHLIGHTS
Simplescratchingrelievesitchingbecauseitactivateslarge,fastconductingafferentsthatgatetransmissionin
thedorsalhorninamanneranalogoustotheinhibitionofpainbystimulationofsimilarafferents.
Antihistaminesareprimarilyeffectiveinreducingpruritusassociatedwithanallergicreaction.Inamouse
modelexhibitingscratchingbehaviorinresponsetoactivationofPAR2,treatmentwithaB2receptor
antagonistreducedthescratchingbehavior.B2receptorantagonistsmaybeausefultherapyfortreating
pruriginousconditions.
Nerveendingsalsohaveavarietyofreceptorsthatrespondtoimmunemediatorsthatarereleasedinresponse
totissueinjury.TheseincludeB1andB2receptors(bradykinin),prostanoidreceptors(prostaglandins),and
cytokinereceptors(interleukins).Thesereceptorsmediateinflammatorypain.
THERMORECEPTORS
InnocuouscoldreceptorsorcoolreceptorsareondendriticendingsofAandCfibers,whereasinnocuous
warmthreceptorsareonCfibers.Mappingexperimentsshowthattheskinhasdiscretecoldandheat
sensitivespots.Thereare410timesasmanycoldsensitiveasheatsensitivespots.
Thethresholdforactivationofwarmthreceptorsis30C,andtheyincreasetheirfiringrateastheskin
temperatureincreasesto46C.Coldreceptorsareinactiveattemperaturesof40C,butthensteadilyincrease
theirfiringrateasskintemperaturefallstoabout24C.Asskintemperaturefurtherdecreases,thefiringrateof
coldreceptorsdecreasesuntilthetemperaturereaches10C.Belowthattemperature,theyareinactiveand
coldbecomesaneffectivelocalanesthetic.
ThereceptorthatisactivatedbymoderatecoldisTRPM8.TheMreferstomenthol,theingredientinmint
thatgivesititscooltaste.TRPV4receptorsareactivatedbywarmtemperaturesupto34CTRPV3
receptorsrespondtoslightlyhighertemperaturesof3539C.

GENERATIONOFIMPULSESINCUTANEOUSRECEPTORS
Thewaythatsensoryreceptorsgenerateactionpotentialsinthenervesthatinnervatethemvariesbasedonthe
complexityofthesenseorgan.Intheskin,thePaciniancorpusclehasbeenstudiedinsomedetail.Themyelin
sheathofthesensorynervebeginsinsidethecorpuscle(Figure83).ThefirstnodeofRanvierisalsolocated
insidethesecondisusuallynearthepointatwhichthenervefiberleavesthecorpuscle.
FIGURE83

DemonstrationthatthegeneratorpotentialinaPaciniancorpuscleoriginatesintheunmyelinatednerve
terminal.Theelectricalresponsestopressures(blackarrow)of1,2,3,and4areshown.Thestrongest
stimulusproducedanactionpotentialinthesensorynerve,originatinginthecenterofthecorpuscle.
(ReproducedwithpermissionfromWaxmanSG:ClinicalNeuroanatomy,26thed.NewYork,NY:McGraw
Hill2010.)

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GENERATORPOTENTIALS
WhenasmallamountofpressureisappliedtothePaciniancorpuscle,anonpropagateddepolarizingpotential
resemblinganexcitatorypostsynapticpotential(EPSP)isrecorded.Thisiscalledthegeneratorpotentialor
receptorpotential(Figure83).Asthepressureisincreased,themagnitudeofthereceptorpotentialis
increased.Thereceptorthereforeconvertsmechanicalenergyintoanelectricalresponse,themagnitudeof
whichisproportionaltotheintensityofthestimulus.Thus,theresponsesaredescribedasgradedpotentials
ratherthanallornoneasisthecaseforanactionpotential.Whenthemagnitudeofthegeneratorpotential
reachesabout10mV,anactionpotentialisproducedatthefirstnodeofRanvier.Thenervethenrepolarizes.
Ifthegeneratorpotentialisgreatenough,theneuronfiresagainassoonasitrepolarizes,anditcontinuesto
fireaslongasthegeneratorpotentialislargeenoughtobringthemembranepotentialofthenodetothefiring
level.Thus,thenodeconvertsthegradedresponseofthereceptorintoactionpotentials,thefrequencyof
whichisproportionaltothemagnitudeoftheappliedstimulus.

SENSORYCODING
Convertingareceptorstimulustoarecognizablesensationistermedsensorycoding.Allsensorysystems
codeforfourelementaryattributesofastimulus:modality,location,intensity,andduration.Modalityisthe
typeofenergytransmittedbythestimulus.Locationisthesiteonthebodyorspacewherethestimulus
originated.Intensityissignaledbytheresponseamplitudeorfrequencyofactionpotentialgeneration.
Durationreferstothetimefromstarttoendofaresponseinthereceptor.Theseattributesofsensorycoding
areshownforthemodalityoftouchinFigure81.
Whenthenervefromaparticularsensoryreceptorisstimulated,thesensationevokedisthatforwhichthe
receptorisspecializednomatterhoworwherealongthenervetheactivityisinitiated.Thisprinciple,first
enunciatedbyJohannesMllerin1835,hasbeencalledthelawofspecificnerveenergies.Forexample,if
thesensorynervefromaPaciniancorpuscleinthehandisstimulatedbypressureattheelboworbyirritation
fromatumorinthebrachialplexus,thesensationevokedistouch.Thegeneralprincipleofspecificnerve
energiesremainsoneofthecornerstonesofsensoryphysiology.
MODALITY
Humanshavefourbasicclassesofreceptorsbasedontheirsensitivitytoonepredominantformofenergy:
mechanical,thermal,electromagnetic,orchemical.Theparticularformofenergytowhichareceptorismost
sensitiveiscalleditsadequatestimulus.Theadequatestimulusfortherodsandconesintheeye,for
example,islight(anexampleofelectromagneticenergy).Receptorsdorespondtoformsofenergyotherthan
theiradequatestimuli,butthethresholdforthesenonspecificresponsesismuchhigher.Pressureonthe
eyeballwillstimulatetherodsandcones,forexample,butthethresholdofthesereceptorstopressureismuch
higherthanthethresholdofthepressurereceptorsintheskin.
LOCATION
Thetermsensoryunitreferstoasinglesensoryaxonandallofitsperipheralbranches.Thesebranchesvary
innumberbutmaybenumerous,especiallyinthecutaneoussenses.Thereceptivefieldofasensoryunitis
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thespatialdistributionfromwhichastimulusproducesaresponseinthatunit(Figure81).Representationof
thesensesintheskinispunctate.Iftheskiniscarefullymapped,millimeterbymillimeter,withafinehair,a
sensationoftouchisevokedfromspotsoverlyingthesetouchreceptors.Noneisevokedfromtheintervening
areas.Similarly,temperaturesensationsandpainareproducedbystimulationoftheskinonlyoverthespots
wherethereceptorsforthesemodalitiesarelocated.Inthecorneaandadjacentscleraoftheeye,thesurface
areasuppliedbyasinglesensoryunitis50200mm2.Theareasuppliedbyonesensoryunitusuallyoverlaps
andinterdigitateswiththeareassuppliedbyothers.
Oneofthemostimportantmechanismsthatenablelocalizationofastimulussiteislateralinhibition.
Informationfromsensoryneuronswhosereceptorsareattheperipheraledgeofthestimulusisinhibited
comparedtoinformationfromthesensoryneuronsatthecenterofthestimulus.Thus,lateralinhibition
enhancesthecontrastbetweenthecenterandperipheryofastimulatedareaandincreasestheabilityofthe
braintolocalizeasensoryinput.Lateralinhibitionunderliestwopointdiscrimination(seeClinicalBox8
2).
INTENSITY
Theintensityofsensationisdeterminedbytheamplitudeofthestimulusappliedtothereceptor.Thisis
illustratedinFigure84.Asagreaterpressureisappliedtotheskin,thereceptorpotentialinthe
mechanoreceptorincreases(notshown),andthefrequencyoftheactionpotentialsinasingleaxon
transmittinginformationtotheCNSisalsoincreased.Inadditiontoincreasingthefiringrateinasingleaxon,
thegreaterintensityofstimulationalsowillrecruitmorereceptorsintothereceptivefield.
FIGURE84

Relationshipbetweenstimulusandimpulsefrequencyinanafferentfiber.Actionpotentialsinanafferent
fiberfromamechanoreceptorofasinglesensoryunitincreaseinfrequencyasbranchesoftheafferentneuron
arestimulatedbypressureofincreasingmagnitude.(ReproducedwithpermissionfromWidmaierEP,RaffH,
StrangKT:VandersHumanPhysiology.11thedition.NewYork,NY:McGrawHill2008.)

CLINICALBOX82NeurologicExam
Thesizeofthereceptivefieldsforlighttouchcanbemeasuredbythetwopointthresholdtest.Inthis
procedure,thetwopointsonapairofcalipersaresimultaneouslypositionedontheskinandonedetermines
theminimumdistancebetweenthetwocaliperpointsthatcanbeperceivedasseparatepointsofstimulation.
Thisiscalledthetwopointdiscriminationthreshold.Ifthedistanceisverysmall,eachcaliperpointis
touchingthereceptivefieldofonlyonesensoryneuron.Ifthedistancebetweenstimulationpointsislessthan
thisthreshold,onlyonepointofstimulationcanbefelt.Thus,thetwopointdiscriminationthresholdisa
measureoftactileacuity.Themagnitudeoftwopointdiscriminationthresholdsvariesfromplacetoplaceon
thebodyandissmallestwheretouchreceptorsaremostabundant.Stimuluspointsontheback,forinstance,
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mustbeseparatedbyatleast65mmbeforetheycanbedistinguishedasseparate,whereasonthefingertips
twostimuliarerecognizediftheyareseparatedbyaslittleas2mm.Blindindividualsbenefitfromthetactile
acuityoffingertipstofacilitatetheabilitytoreadBraillethedotsformingBraillesymbolsareseparatedby
2.5mm.Twopointdiscriminationisusedtotesttheintegrityofthedorsalcolumn(mediallemniscus)
system,thecentralpathwayfortouchandproprioception.
Vibratorysensibilityistestedbyapplyingavibrating(128Hz)tuningforktotheskinonthefingertip,tipof
thetoe,orbonyprominencesofthetoes.Thenormalresponseisabuzzingsensation.Thesensationismost
markedoverbones.Thetermpallesthesiaisalsousedtodescribethisabilitytofeelmechanicalvibrations.
Thereceptorsinvolvedarethereceptorsfortouch,especiallyPaciniancorpuscles,butatimefactorisalso
necessary.Apatternofrhythmicpressurestimuliisinterpretedasvibration.Theimpulsesresponsibleforthe
vibratingsensationarecarriedinthedorsalcolumns.Degenerationofthispartofthespinalcordoccursin
poorlycontrolleddiabetes,perniciousanemia,vitaminB12deficiencies,orearlytabesdorsalis.Elevationof
thethresholdforvibratorystimuliisanearlysymptomofthisdegeneration.Vibratorysensationand
proprioceptionarecloselyrelatedwhenoneisdiminished,soistheother.Stereognosisistheperceptionof
theformandnatureofanobjectwithoutlookingatit.Normalpersonscanreadilyidentifyobjectssuchaskeys
andcoinsofvariousdenominations.Thisabilitydependsonrelativelyintacttouchandpressuresensationand
iscompromisedwhenthedorsalcolumnsaredamaged.Theinabilitytoidentifyanobjectbytouchiscalled
tactileagnosia.Italsohasalargecorticalcomponentimpairedstereognosisisanearlysignofdamagetothe
cerebralcortexandsometimesoccursintheabsenceofanydetectabledefectintouchandpressuresensation
whenthereisalesionintheprimarysensorycortex.Stereognosiacanalsobeexpressedbythefailureto
identifyanobjectbysight(visualagnosia),theinabilitytoidentifysoundsorwords(auditoryagnosia)or
color(coloragnosia),ortheinabilitytoidentifythelocationorpositionofanextremity(positionagnosia).
DURATION
Asthestrengthofastimulusisincreased,ittendstospreadoveralargeareaandgenerallynotonlyactivates
thesenseorgansimmediatelyincontactwithitbutalsorecruitsthoseinthesurroundingarea.Furthermore,
weakstimuliactivatethereceptorswiththelowestthresholds,andstrongerstimulialsoactivatethosewith
higherthresholds.Someofthereceptorsactivatedarepartofthesamesensoryunit,andimpulsefrequencyin
theunitthereforeincreases.Becauseofoverlapandinterdigitationofoneunitwithanother,however,
receptorsofotherunitsarealsostimulated,andconsequentlymoreunitsfire.Inthisway,moreafferent
pathwaysareactivated,whichisinterpretedinthebrainasanincreaseinintensityofthesensation.
Ifastimulusofconstantstrengthismaintainedonasensoryreceptor,thefrequencyoftheactionpotentialsin
itssensorynervedeclinesovertime.Thisphenomenonisknownasreceptoradaptationordesensitization.
Thedegreetowhichadaptationoccursvariesfromonesensetoanother.Receptorscanbeclassifiedinto
rapidlyadapting(phasic)receptorsandslowlyadapting(tonic)receptors.Thisisillustratedfordifferent
typesoftouchreceptorsinFigure81.MeissnerandPaciniancorpusclesareexamplesofrapidlyadapting
receptors,andMerkelcellsandRuffiniendingsareexamplesofslowlyadaptingreceptors.Otherexamplesof
slowlyadaptingreceptorsaremusclespindlesandnociceptors.Differenttypesofsensoryadaptationlikely
havesomevaluetotheindividual.Lighttouchwouldbedistractingifitwerepersistentand,conversely,slow
adaptationofspindleinputisneededtomaintainposture.Similarly,inputfromnociceptorsprovidesawarning
thatitwouldloseitsvalueifitisadaptedanddisappeared.
NEUROLOGICEXAM
Thesensorycomponentofaneurologicexamincludesanassessmentofvarioussensorymodalitiesincluding
touch,proprioception,vibratorysense,andpain.Corticalsensoryfunctioncanbetestedbyplacingfamiliar
objectsinapatientshandsandaskinghimorhertoidentifyitwiththeeyesclosed.ClinicalBox82
describessomeofthecommonassessmentsmadeinaneurologicexam.

PAIN
Oneofthemostcommonreasonsanindividualseekstheadviceofaclinicianisbecauseheorsheisinpain.
TheEnglishneurophysiologistSirCharlesSherringtonreferredtopainasthephysicaladjunctofan
imperaprotectivereflex.Painfulstimuligenerallyinitiatepotentwithdrawalandavoidanceresponses.Pain
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differsfromothersensationsinthatitsoundsawarningthatsomethingiswrong,preemptsothersignals,and
isassociatedwithanunpleasantaffect.Itisimmenselycomplexbecausewhentissueisdamaged,central
nociceptivepathwaysaresensitizedandreorganized,whichleadstopersistentorchronicpain(seeClinical
Box83).
CLINICALBOX83ChronicPain
A2009reportinScientificAmericanindicatedthat1020%oftheUSandEuropeanpopulationsexperience
chronicpain59%oftheseindividualsarewomen.Basedonasurveyofprimarycareclinicians,only15%
indicatedthattheyfeltcomfortabletreatingpatientswithchronicpainand41%saidtheywaiteduntilpatients
specificallyrequestedopioidpainkillersbeforeprescribingthem.Nearly20%ofadultswithchronicpain
indicatedthattheyhavevisitedanalternativemedicinetherapist.Riskfactorsforchronicneckandbackpain
includeaging,beingfemale,anxiety,repetitivework,obesity,depression,heavylifting,andnicotineuse.One
exampleofchronicpainisneuropathicpainthatmayoccurwhennervefibersareinjured.Nervedamagecan
causeaninflammatoryresponseduetoactivationofmicrogliainthespinalcord.Neuropathicpainis
excruciatinganditisadifficultconditiontotreat.Theresultingpainlastsmuchlongerthantheinjuryitself.
Forexample,incausalgia,aspontaneousburningpainoccurslongafterseeminglytrivialinjuries.Thepainis
oftenaccompaniedbyhyperalgesiaandallodynia.Reflexsympatheticdystrophyisoftenpresentaswell.In
thiscondition,theskinintheaffectedareaisthinandshiny,andthereisincreasedhairgrowth.Thismay
resultbecauseofsproutingandeventualovergrowthofnoradrenergicsympatheticnervefibersintothedorsal
rootgangliaofthesensorynervesfromtheinjuredarea.Sympatheticdischargethenbringsonpain.Thus,it
appearsthattheperipheryhasbeenshortcircuitedandthattherelevantalteredfibersarebeingstimulatedby
norepinephrineatthedorsalrootganglionlevel.
THERAPEUTICHIGHLIGHTS
Chronicpainisoftenrefractorytomostconventionaltherapiessuchasnonsteroidalantiinflammatory
drugsandevenopioids.Inneweffortstotreatchronicpain,sometherapiesfocusonsynaptictransmissionin
centralnociceptivepathwaysandperipheralsensorytransductionmechanisms.TRPV1,acapsaicinreceptor,
isactivatedbynoxiousstimulisuchasheat,protons,andproductsofinflammation.Capsaicintransdermal
patchesorcreamsreducepainbyexhaustingthesupplyofsubstancePinnerves.Nav1.8(atetrodotoxin
resistantvoltagegatedsodiumchannel)isuniquelyassociatedwithnociceptiveneuronsindorsalrootganglia.
Lidocaineandmexiletineareusefulinsomecasesofchronicpainandmayactbyblockingthischannel.
Ziconotide,avoltagegatedNtypeCa2+ channelblocker,hasbeenapprovedforintrathecalanalgesiain
patientswithrefractorychronicpain.GabapentinisananticonvulsantdrugthatisananalogofGABAithas
beenshowntobeeffectiveintreatmentofneuropathicandinflammatorypainbyactingonvoltagegated
Ca2+ channels.Twootheranticonvulsantdrugs,topiramateandvalproate(valproicacid),blockvoltage
gatedNa+ channelsandareusedtotreatmigraineheadaches.NMDA(NmethylDaspartate)receptor
antagonistscanbecoadministeredwithanopioidtoreducetolerancetoanopioid.Endogenouscannabinoids
haveanalgesicactionsinadditiontotheireuphoriceffects.DrugsthatactonCB2receptorsthataredevoidof
euphoriceffectsareunderdevelopmentforthetreatmentofinflammatoryandneuropathicpain.
CLASSIFICATIONOFPAIN
Forscientificandclinicalpurposes,painisdefinedbytheInternationalAssociationfortheStudyofPain
(IASP)as,anunpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissuedamage,
ordescribedintermsofsuchdamage.ThisistobedistinguishedfromthetermnociceptionthattheIASP
definesastheunconsciousactivityinducedbyaharmfulstimulusappliedtosensereceptors.
Painisfrequentlyclassifiedasphysiologicoracutepainandpathologicorchronicpain,whichincludes
inflammatorypainandneuropathicpain.Acutepaintypicallyhasasuddenonsetandrecedesduringthe
healingprocessitcanberegardedasgoodpainasitservesanimportantprotectivemechanism.The
withdrawalreflexisanexampleoftheexpressionofthisprotectiveroleofpain.
Chronicpaincanbeconsideredbadpainbecauseitpersistslongafterrecoveryfromaninjuryandisoften
refractorytocommonanalgesicagents,includingnonsteroidalantiinflammatorydrugs(NSAIDs)and
opioids.Chronicpaincanresultfromnerveinjury(neuropathicpain)includingdiabeticneuropathy,toxin
inducednervedamage,andischemia.Causalgiaisatypeofneuropathicpain(seeClinicalBox83).
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HYPERALGESIA&ALLODYNIA
Painisoftenaccompaniedbyhyperalgesiaandallodynia.Hyperalgesiaisanexaggeratedresponsetoa
noxiousstimulus,andallodyniaisasensationofpaininresponsetoanormallyinnocuousstimulus.An
exampleofthelatteristhepainfulsensationfromawarmshowerwhentheskinisdamagedbysunburn.
Hyperalgesiaandallodyniasignifyincreasedsensitivityofnociceptiveafferentfibers.Figure85showshow
chemicalsreleasedatthesiteofinjurycanfurtherdirectlyactivatereceptorsonsensorynerveendingsleading
toinflammatorypain.InjuredcellsalsoreleasechemicalssuchasK+ thatdirectlydepolarizenerveterminals,
makingnociceptorsmoreresponsive(sensitization).InjuredcellsalsoreleasebradykininandsubstanceP,
whichcanfurthersensitizenociceptiveterminals.Histamineisreleasedfrommastcells,serotonin(5HT)
fromplatelets,andprostaglandinsfromcellmembranes,allcontributingtotheinflammatoryprocessandthey
activateorsensitizethenociceptors.Somereleasedsubstancesactbyreleasinganotherone(eg,bradykinin
activatesbothAandCnerveendingsandincreasessynthesisandreleaseofprostaglandins).ProstaglandinE2
(acyclooxygenasemetaboliteofarachidonicacid)isreleasedfromdamagedcellsandproduceshyperalgesia.
ThisiswhyaspirinandotherNSAIDs(nonselectiveinhibitorsofcyclooxygenase)alleviatepain.
FIGURE85

Chemicalmediatorsarereleasedinresponsetotissuedamageandcansensitizeordirectlyactivate
nociceptors.Thesefactorscontributetohyperalgesiaandallodynia.Tissueinjuryreleasesbradykininand
prostaglandinsthatsensitizeoractivatenociceptors,whichinturnreleasesubstancePandcalcitoningene
relatedpeptide(CGRP).SubstancePactsonmastcellstocausedegranulationandreleasehistamine,which
activatesnociceptors.SubstancePcausesplasmaextravasationandCGRPdilatesbloodvesselstheresulting
edemacausesadditionalreleaseofbradykinin.Serotonin(5HT)isreleasedfromplateletsandactivates
nociceptors.(ReproducedwithpermissionfromLembeckF:CIBAFoundationSymposium.Summit,NJ:
PitmanMedical1981.)

Inadditiontosensitizationofnerveendingsbychemicalmediators,severalotherchangesoccurwithinthe
peripheryandtheCNSthatcancontributetothechronicpain.TheNGFreleasedbytissuedamageispicked
upbynerveterminalsandtransportedretrogradelytocellbodiesindorsalrootgangliawhereitcanaltergene
expression.TransportmaybefacilitatedbytheactivationofTrkAreceptorsonthenerveendings.Inthedorsal
rootganglia,theNGFincreasesproductionofsubstancePandconvertsnonnociceptiveneuronstonociceptive
neurons(aphenotypicchange).TheNGFalsoinfluencesexpressionofatetrodotoxinresistantvoltagegated
sodiumchannel(Nav1.8)ondorsalrootgangliacells,furtherincreasingactivity.
Damagednervefibersundergosprouting,sofibersfromtouchreceptorssynapseonspinaldorsalhornneurons
thatnormallyreceiveonlynociceptiveinput(seebelow).Thiscanexplainwhyinnocuousstimulicaninduce
painafterinjury.ThecombinedreleaseofsubstancePandglutamatefromnociceptiveafferentsinthespinal
cordcausesexcessiveactivationofNMDA(NmethylDaspartate)receptorsonspinalneurons,a
phenomenoncalledwindupthatleadstoincreasedactivityinpaintransmittingpathways.Anotherchange
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inthespinalcordisduetotheactivationofmicroglianearafferentnerveterminalsinthespinalcordbythe
releaseoftransmittersfromsensoryafferents.This,inturn,leadstothereleaseofproinflammatorycytokines
andchemokinesthatmodulatepainprocessingbyaffectingpresynapticreleaseofneurotransmittersand
postsynapticexcitability.ThereareP2Xreceptorsonmicrogliaantagonistsofthesereceptorsmaybeauseful
therapyfortreatmentofchronicpain.
DEEP&VISCERALPAIN
Themaindifferencebetweensuperficialanddeeporvisceralpainisthenatureofthepainevokedbynoxious
stimuli.ThisisprobablyduetoarelativedeficiencyofAnervefibersindeepstructures,sothereislittle
rapid,sharppain.Inaddition,deeppainandvisceralpainarepoorlylocalized,nauseating,andfrequentlyare
accompaniedbysweatingandchangesinbloodpressure.Paincanbeelicitedexperimentallyfromthe
periosteumandligamentsbyinjectinghypertonicsalineintothem.Thepainproducedinthismannerinitiates
reflexcontractionofnearbyskeletalmuscles.Thisreflexcontractionissimilartothemusclespasmassociated
withinjuriestobones,tendons,andjoints.Thesteadilycontractingmusclesbecomeischemic,andischemia
stimulatesthepainreceptorsinthemuscles.Thepaininturninitiatesmorespasm,settingupaviciouscycle.
Inadditiontobeingpoorlylocalized,unpleasant,andassociatedwithnauseaandautonomicsymptoms,
visceralpainoftenradiatesorisreferredtootherareas.Theautonomicnervoussystem,suchasthesomatic,
hasafferentcomponents,centralintegratingstations,andeffectorpathways.Thereceptorsforpainandthe
othersensorymodalitiespresentinthevisceraaresimilartothoseinskin,buttherearemarkeddifferencesin
theirdistribution.Therearenoproprioceptorsintheviscera,andfewtemperatureandtouchreceptors.
Nociceptorsarepresent,althoughtheyaremoresparselydistributedthaninsomaticstructures.
AfferentfibersfromvisceralstructuresreachtheCNSviasympatheticandparasympatheticnerves.Theircell
bodiesarelocatedinthedorsalrootgangliaandthehomologouscranialnerveganglia.Specifically,thereare
visceralafferentsinthefacial,glossopharyngeal,andvagusnervesinthethoracicandupperlumbardorsal
rootsandinthesacraldorsalroots.
Asalmosteveryoneknowsfrompersonalexperience,visceralpaincanbeverysevere.Thereceptorsinthe
wallsofthehollowvisceraareespeciallysensitivetodistensionoftheseorgans.Suchdistensioncanbe
producedexperimentallyinthegastrointestinaltractbyinflationofaswallowedballoonattachedtoatube.
Thisproducespainthatwaxesandwanes(intestinalcolic)astheintestinecontractsandrelaxesonthe
balloon.Similarcolicisproducedinintestinalobstructionbythecontractionsofthedilatedintestineabovethe
obstruction.Whenavisceralorganisinflamedorhyperemic,relativelyminorstimulicauseseverepain,a
formofhyperalgesia.
REFERREDPAIN
Irritationofavisceralorganfrequentlyproducespainthatisfeltnotatthatsitebutinasomaticstructurethat
maybesomedistanceaway.Suchpainissaidtobereferredtothesomaticstructure(referredpain).
Knowledgeofthecommonsitesofpainreferralfromeachofthevisceralorgansisofimportancetoa
clinician.Oneofthebestknownexamplesisreferralofcardiacpaintotheinneraspectoftheleftarm.Other
examplesincludepaininthetipoftheshouldercausedbyirritationofthecentralportionofthediaphragmand
paininthetesticleduetodistensionoftheureter.Additionalinstancesaboundinthepracticesofmedicine,
surgery,anddentistry.However,sitesofreferencearenotstereotyped,andunusualreferencesitesoccurwith
considerablefrequency.Cardiacpain,forinstance,maybereferredtotherightarm,theabdominalregion,or
eventheback,neck,orjaw.
Whenpainisreferred,itisusuallytoastructurethatdevelopedfromthesameembryonicsegmentor
dermatomeasthestructureinwhichthepainoriginates.Forexample,theheartandthearmhavethesame
segmentalorigin,andthetesticlemigratedwithitsnervesupplyfromtheprimitiveurogenitalridgefrom
whichthekidneyandureteralsodeveloped.
Thebasisforreferredpainmaybeconvergenceofsomaticandvisceralpainfibersonthesamesecondorder
neuronsinthedorsalhornthatprojecttothethalamusandthentothesomatosensorycortex(Figure86).This
iscalledtheconvergenceprojectiontheory.Somaticandvisceralneuronsconvergeintheipsilateraldorsal
horn.Thesomaticnociceptivefibersnormallydonotactivatethesecondorderneurons,butwhenthevisceral
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stimulusisprolonged,facilitationofthesomaticfiberendingsoccurs.Theynowstimulatethesecondorder
neurons,andofcoursethebraincannotdeterminewhetherthestimuluscamefromthevisceraorfromthearea
ofreferral.
FIGURE86

Schematicillustrationoftheconvergenceprojectiontheoryforreferredpainanddescendingpathways
involvedinpaincontrol.Thebasisforreferredpainmaybeconvergenceofsomaticandvisceralpainfibers
onthesamesecondorderneuronsinthedorsalhornofthespinalcordthatprojecthigherbrainregions.The
periaqueductalgrayisapartofadescendingpathwaythatincludesserotonergicneuronsinthenucleusraphe
magnusandcatecholaminergicneuronsintherostralventromedialmedullatomodulatepaintransmissionby
inhibitionofprimaryafferenttransmissioninthedorsalhorn.

SOMATOSENSORYPATHWAYS
Thesensationevokedbyimpulsesgeneratedinasensoryreceptordependsinpartonthespecificpartofthe
braintheyultimatelyactivate.Theascendingpathwaysfromsensoryreceptorstothecortexaredifferentfor
thevarioussensations.Belowisacomparisonoftheascendingsensorypathwaythatmediatestouch,vibratory
sense,andproprioception(dorsalcolumnmediallemniscalpathway)andthatwhichmediatespainand
temperature(ventrolateralspinothalamicpathway).
DORSALCOLUMNPATHWAY
Theprincipalpathwaystothecerebralcortexfortouch,vibratorysense,andproprioceptionareshownin
Figure87.Fibersmediatingthesesensationsascendipsilaterallyinthedorsalcolumnsofthespinalcordto
themedulla,wheretheysynapseinthegracilusandcuneatenuclei.Thesecondorderneuronsfromthese
nucleicrossthemidlineandascendinthemediallemniscustoendinthecontralateralventralposterior
lateral(VPL)nucleusandrelatedspecificsensoryrelaynucleiofthethalamus.Thisascendingsystemis
calledthedorsalcolumnormediallemniscalsystem.Thefiberswithinthedorsalcolumnpathwayarejoined
inthebrainstembyfibersmediatingsensationfromthehead.Touchandproprioceptionfromtheheadare
relayedmostlyviathemainsensoryandmesencephalicnucleiofthetrigeminalnerve.
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FIGURE87

Ascendingtractscarryingsensoryinformationfromperipheralreceptorstothecerebralcortex.A)
Dorsalcolumnpathwaymediatestouch,vibratorysense,andproprioception.Sensoryfibersascend
ipsilaterallyviathespinaldorsalcolumnstomedullarygracilusandcuneatenucleifromtherethefiberscross
themidlineandascendinthemediallemniscustothecontralateralthalamicventralposteriorlateral(VPL)and
thentotheprimarysomatosensorycortex.B)Ventrolateralspinothalamictractmediatespainandtemperature.
Thesesensoryfibersterminateinthedorsalhornandprojectionsfromtherecrossthemidlineandascendin
theventrolateralquadrantofthespinalcordtotheVPLandthentotheprimarysomatosensorycortex.

SomatotopicOrganization

Withinthedorsalcolumns,fibersarisingfromdifferentlevelsofthecordaresomatotopicallyorganized
(Figure87).Specifically,fibersfromthesacralcordarepositionedmostmediallyandthosefromthecervical
cordarepositionedmostlaterally.Thisarrangementcontinuesinthemedullawithlowerbody(eg,foot)
representationinthegracilusnucleusandupperbody(eg,finger)representationincuneatenucleus.The
mediallemniscusisorganizeddorsaltoventralrepresentingfromnecktofoot.
Somatotopicorganizationcontinuesthroughthethalamusandcortex.TheVPLthalamicneuronscarrying
sensoryinformationprojectinahighlyspecificwaytotheprimarysomatosensorycortexinthepostcentral
gyrusoftheparietallobe(Figure88).Thearrangementofprojectionstothisregionissuchthatthepartsof
thebodyarerepresentedinorderalongthepostcentralgyrus,withthelegsontopandtheheadatthefootof
thegyrus.Notonlyistheredetailedlocalizationofthefibersfromthevariouspartsofthebodyinthe
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postcentralgyrus,butalsothesizeofthecorticalreceivingareaforimpulsesfromaparticularpartofthebody
isproportionaltotheuseofthepart.Therelativesizesofthecorticalreceivingareasareshowndramaticallyin
Figure89,inwhichtheproportionsofthehomunculushavebeendistortedtocorrespondtothesizeofthe
corticalreceivingareasforeach.Notethatthecorticalareasforsensationfromthetrunkandbackaresmall,
whereasverylargeareasareconcernedwithimpulsesfromthehandandthepartsofthemouthconcernedwith
speech.
FIGURE88

Alateralviewofthelefthemisphereshowingsomeprincipalcorticalareasandtheirfunctional
correlatesinthehumanbrain.Theprimarysomatosensoryareaisinthepostcentralgyrusoftheparietal
lobe,andtheprimarymotorcortexisintheprecentralgyrus.(ReproducedwithpermissionfromWaxmanSG:
ClinicalNeuroanatomy,26thed.NewYork,NY:McGrawHill2010.)

FIGURE89

Sensoryhomunculus,drawnoverlyingacoronalsectionthroughthepostcentralgyrus.Thepartsofthe
bodyarerepresentedinorderalongthepostcentralgyrus,withthelegsontopandtheheadatthefootofthe
gyrus.Thesizeofthecorticalreceivingareaforimpulsesfromaparticularpartofthebodyisproportionateto
theuseofthepart.Gen.,genitalia.

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Studiesofthesensoryreceivingareaemphasizetheverydiscretenatureofthepointforpointlocalizationof
peripheralareasinthecortexandprovidefurtherevidenceforthegeneralvalidityofthelawofspecificnerve
energies.Stimulationofthevariouspartsofthepostcentralgyrusgivesrisetosensationsprojectedto
appropriatepartsofthebody.Thesensationsproducedareusuallynumbness,tingling,orasenseof
movement,butwithfineenoughelectrodesithasbeenpossibletoproducerelativelypuresensationsoftouch,
warmth,andcold.Thecellsinthepostcentralgyrusareorganizedinverticalcolumns.Thecellsinagiven
columnareallactivatedbyafferentsfromagivenpartofthebody,andallrespondtothesamesensory
modality.
Inadditiontotheprimarysomatosensorycortex,therearetwoothercorticalregionsthatcontributetothe
integrationofsensoryinformation.Thesensoryassociationareaislocatedintheparietalcortexandthe
secondarysomatosensorycortexislocatedinthewallofthelateralfissure(alsocalledsylvianfissure)that
separatesthetemporalfromthefrontalandparietallobes.Theseregionsreceiveinputfromtheprimary
somatosensorycortex.
Consciousawarenessofthepositionsofthevariouspartsofthebodyinspacedependsinpartonimpulses
fromsensoryreceptorsinandaroundthejoints.Impulsesfromthesereceptors,fromtouchreceptorsinthe
skinandothertissues,andfrommusclespindlesaresynthesizedinthecortexintoaconsciouspictureofthe
positionofthebodyinspace.
VENTROLATERALSPINOTHALAMICTRACT
Fibersfromnociceptorsandthermoreceptorssynapseonneuronsinthedorsalhornofthespinalcord.The
axonsfromthesedorsalhornneuronscrossthemidlineandascendintheventrolateralquadrantofthespinal
cord,wheretheyformtheventrolateralspinothalamicpathway(Figure87).Fiberswithinthistractsynapsein
theVPL.Somedorsalhornneuronsthatreceivenociceptiveinputsynapseinthereticularformationofthe
brainstem(spinoreticularpathway)andthenprojecttothecentrolateralnucleusofthethalamus.
Positronemissiontomographic(PET)andfunctionalmagneticresonanceimaging(fMRI)studiesinhealthy
humansindicatethatpainactivatestheprimaryandsecondarysomatosensorycortexandthecingulategyrus
onthesideoppositethestimulus.Inaddition,theamygdala,frontallobe,andtheinsularcortexareactivated.
Thesetechnologieswereimportantindistinguishingtwocomponentsofpainpathways.Researchersfound
thatnoxiousstimulithatdidnotinduceachangeinaffectcausedanincreasedmetabolismintheprimary
somatosensorycortex,whereasstimulithatelicitedmotivationalaffectiveresponsesactivatedalargerportion
ofthecortex.Thisshowedthatthepathwaytotheprimarysomatosensorycortexisresponsibleforthe
discriminativeaspectofpain.Incontrast,thepathwaythatincludessynapsesinthebrainstemreticular
formationandcentrolateralthalamicnucleusprojectstothefrontallobe,limbicsystem,andinsularcortex.
Thispathwaymediatesthemotivationalaffectivecomponentofpain.
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Visceralsensationtravelsalongthesamecentralpathwaysassomaticsensationinthespinothalamictractsand
thalamicradiations,andthecorticalreceivingareasforvisceralsensationareintermixedwiththesomatic
receivingareas.
CORTICALPLASTICITY
Itisnowclearthattheextensiveneuronalconnectionsdescribedabovearenotinnateandimmutablebutcan
bechangedrelativelyrapidlybyexperiencetoreflecttheuseoftherepresentedarea.ClinicalBox84
describesremarkablechangesincorticalandthalamicorganizationthatoccurinresponsetolimbamputation
toleadtothephenomenonofphantomlimbpain.
CLINICALBOX84PhantomLimbPain
In1551,AmbroisePare,amilitarysurgeon,wrotethepatients,longaftertheamputationismade,saythey
stillfeelpainintheamputatedpart.Ofthistheycomplainstrongly,athingworthyofwonderandalmost
incredibletopeoplewhohavenotexperiencedthis.Thisisperhapstheearliestdescriptionofphantomlimb
pain.Between50%and80%ofamputeesexperiencephantomsensations,usuallypain,intheregionoftheir
amputatedlimb.Phantomsensationsmayalsooccuraftertheremovalofbodypartsotherthanthelimbs,for
example,afteramputationofthebreast,extractionofatooth(phantomtoothpain),orremovalofaneye
(phantomeyesyndrome).Numeroustheorieshavebeenevokedtoexplainthisphenomenon.Thecurrent
theoryisbasedonevidencethatthebraincanreorganizeifsensoryinputiscutoff.Theventralposterior
thalamicnucleusisoneexamplewherethischangecanoccur.Inpatientswhohavehadtheirlegamputated,
singleneuronrecordingsshowthatthethalamicregionthatoncereceivedinputfromthelegandfootnow
respondtostimulationofthestump(thigh).Othershavedemonstratedremappingofthesomatosensorycortex.
Forexample,insomeindividualswhohavehadanarmamputated,strokingdifferentpartsofthefacecanlead
tothefeelingofbeingtouchedintheareaofthemissinglimb.
THERAPEUTICHIGHLIGHTS
Thereissomeevidencethattheuseofepiduralanesthesiaduringtheamputationsurgerycanpreventthe
acutepainassociatedwiththesurgery,therebyreducingtheneedforopioidtherapyintheimmediate
postoperativeperiod.Areducedincidenceofphantompainfollowingthisanestheticprocedurewasalso
reported.Spinalcordstimulationhasbeenshowntobeaneffectivetherapyforphantompain.Electric
currentispassedthroughanelectrodethatisplacednexttothespinalcordtostimulatespinalpathways.This
interfereswiththeimpulsesascendingtothebrainandlessensthepainfeltinthephantomlimb.Instead,
amputeesfeelatinglingsensationinthephantomlimb.
Numerousanimalstudiespointtodramaticreorganizationofcorticalstructures.Ifadigitisamputatedina
monkey,thecorticalrepresentationoftheneighboringdigitsspreadsintothecorticalareathatwasformerly
occupiedbytherepresentationoftheamputateddigit.Conversely,ifthecorticalarearepresentingadigitis
removed,thesomatosensorymapofthedigitmovestothesurroundingcortex.Extensive,longterm
deafferentationoflimbsleadstoevenmoredramaticshiftsinsomatosensoryrepresentationinthecortex,with,
forexample,thehandcorticalarearespondingtotouchingtheface.Theexplanationoftheseshiftsappearsto
bethatcorticalconnectionsofsensoryunitstothecortexhaveextensiveconvergenceanddivergence,with
connectionsthatcanbecomeweakwithdisuseandstrongwithuse.
Plasticityofthistypeoccursnotonlywithinputfromcutaneousreceptorsbutalsowithinputinothersensory
systems.Forexample,incatswithsmalllesionsoftheretina,thecorticalareafortheblindspotbeginsto
respondtolightstrikingotherareasoftheretina.Developmentoftheadultpatternofretinalprojectionstothe
visualcortexisanotherexampleofthisplasticity.Atamoreextremelevel,experimentallyroutingvisualinput
totheauditorycortexduringdevelopmentcreatesvisualreceptivefieldsintheauditorysystem.
PETscanninginhumansalsodocumentsplasticchanges,sometimesfromonesensorymodalitytoanother.
Thus,forexample,tactileandauditorystimuliincreasemetabolicactivityinthevisualcortexinblind
individuals.Conversely,deafindividualsrespondfasterandmoreaccuratelythannormalindividualsto
movingstimuliinthevisualperiphery.Plasticityalsooccursinthemotorcortex.Thesefindingsillustratethe
malleabilityofthebrainanditsabilitytoadapt.
EFFECTSOFCNSLESIONS
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ClinicalBox82describessomeofthedeficitsnotedafterdamagewithinthesomatosensorypathways.
ClinicalBox85describesthecharacteristicchangesinsensoryandmotorfunctionsthatoccurinresponseto
spinalhemisection.
Damagetothedorsalcolumnsleadstoipsilaterallossoftheabilitytodetectlighttouch,vibration,and
proprioceptionfrombodystructuresrepresentedcaudaltothelevelofdamage.Damagetotheventrolateral
spinothalamicpathwayleadstocontralaterallossofpainandtemperaturesensationbelowthelevelofthe
lesion.Suchspinaldamagecouldoccurwithapenetratingwoundoratumor.
Lesionsoftheprimarysomatosensorycortexdonotabolishsomaticsensation.Irritationofthisregioncauses
paresthesiaoranabnormalsensationofnumbnessandtinglingonthecontralateralsideofthebody.
Destructivelesionsimpairtheabilitytolocalizenoxiousstimuliintime,space,andintensity.Damagetothe
cingulatecorteximpairstherecognitionoftheaversivenatureofanoxiousstimulus.
Aninfarctinthethalamuscanleadtoalossofsensation.Thalamicpainsyndromeissometimesseenduring
recoveryfromathalamicinfarct.Thesyndromeischaracterizedbychronicpainonthesideofthebody
contralateraltothestroke.
CLINICALBOX85BrownSquardSyndrome
Afunctionalhemisectionofthespinalcordcausesacharacteristicandeasilyrecognizedclinicalpicturethat
reflectsdamagetoascendingsensory(dorsalcolumnpathway,ventrolateralspinothalamictract)and
descendingmotor(corticospinaltract)pathways,whichiscalledtheBrownSquardsyndrome.Thelesion
tofasciculusgracilusorfasciculuscuneatusleadstoipsilaterallossofdiscriminativetouch,vibration,and
proprioceptionbelowthelevelofthelesion.Thelossofthespinothalamictractleadstocontralaterallossof
painandtemperaturesensationbeginningoneortwosegmentsbelowthelesion.Damagetothecorticospinal
tractproducesweaknessandspasticityincertainmusclegroupsonthesamesideofthebody.Althougha
precisespinalhemisectionisrare,thesyndromeisfairlycommonbecauseitcanbecausedbyaspinalcord
tumor,spinalcordtrauma,degenerativediskdisease,andischemia.
THERAPEUTICHIGHLIGHTS
DrugtreatmentsforBrownSquardsyndromearebasedontheetiologyandtimesinceonset.Highdosesof
corticosteroidshavebeenshowntobeofvalueparticularlyifadministeredsoonaftertheonsetofsucha
spinalcordinjury.Corticosteroidsdecreasetheinflammationbysuppressingpolymorphonuclearleukocytes
andreversetheincreaseincapillarypermeability.

MODULATIONOFPAINTRANSMISSION
PROCESSINGINFORMATIONINTHEDORSALHORN
Transmissioninnociceptivepathwayscanbeinterruptedbyactionswithinthedorsalhornofthespinalcordat
thesiteofsensoryafferenttermination.Manypeoplehavelearnedfrompracticalexperiencethatrubbingor
shakinganinjuredareadecreasesthepainduetotheinjury.Thereliefmaybeduetothesimultaneous
activationofinnocuouscutaneousmechanoreceptorswhoseafferentsemitcollateralsthatterminateinthe
dorsalhorn.Theactivityofthesecutaneousmechanosensitiveafferentsmayreducetheresponsivenessof
dorsalhornneuronstotheirinputfromnociceptiveafferentterminals.Thisiscalledthegatecontrol
mechanismofpainmodulationanditservesastherationalebehindtheuseoftranscutaneouselectrical
nervestimulation(TENS)forpainrelief.ThismethoduseselectrodestoactivateAandAfibersinthe
vicinityoftheinjury.
OpioidsareacommonlyusedanalgesicthatcanexerttheireffectsatvariousplacesintheCNS,includingin
thespinalcordanddorsalrootganglia.Figure810showssomeofthevariousmodesofactionofopioidsto
decreasenociceptivetransmission.Thereareinterneuronsinthesuperficialregionsofthedorsalhornthat
containendogenousopioidpeptides(enkephalinanddynorphin).Theseinterneuronsterminateintheregion
ofthedorsalhornwherenociceptiveafferentsterminate.Opioidreceptorsarelocatedontheterminalsof
nociceptivefibersandondendritesofdorsalhornneurons,allowingforbothpresynapticandpostsynaptic
sitesofactionsforopioids.Activationofthepostsynapticopioidreceptorshyperpolarizesthedorsalhorn
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interneuronbycausinganincreaseinK+ conductance.Activationofthepresynapticopioidreceptorsleadsto
adecreaseinCa2+ influx,resultinginadecreaseinreleaseofglutamateandsubstanceP.Togetherthese
actionsreducethedurationoftheEPSPinthedorsalhornneuron.Activationofopioidreceptorsondorsal
rootgangliacellbodiesalsocontributestoreducedtransmissionfromnociceptiveafferents.
FIGURE810

Actionsofopioidstoreducesensorytransmissioninpainpathwaysatthelevelofthedorsalroot
ganglion(DRG)andspinalcorddorsalhornregion.A)Activationofanociceptorleadstothereleaseof
glutamateandneuropeptidesfromitsnerveterminalsthatsynapseonspinothalamictractprojectionneurons.
Thisleadstothedepolarization(activation)ofspinothalamictractprojectionneurons.Enkephalin(ENK)
containinginterneuronsmediatetheireffectsviaopioidreceptorsontheterminalsofnociceptiveafferent
fibersandondendritesofdorsalhornneuronstoexertbothpresynapticandpostsynapticinhibition.B)The
actionofanopioid(eg,morphine)withintheDRGistodecreaseCa2+ influxleadingtoadecreaseinthe
durationoftheinvokedactionpotentialinthenociceptiveneuronandareductionintransmitterreleasefrom
thenociceptiveneuronontoaneuroninthedorsalhorn.Opioidsalsohyperpolarizethemembraneofdorsal
hornneuronbyactivationofaK+ conductanceopioidsalsodecreasetheamplitudeoftheexcitatory
postsynapticpotential(EPSP)producedbystimulationofnociceptors.

Patientswhoreceivelongtermpainmanagementwithmorphinemaybecomeresistanttothedrug,requiring
progressivelyhigherdosesforpainrelief.Thisacquiredtoleranceisdifferentfromaddiction,whichrefersto
apsychologicalcraving.Psychologicaladdictionrarelyoccurswhenmorphineisusedtotreatchronicpain,
providedthepatientdoesnothaveahistoryofdrugabuse.ClinicalBox86describesmechanismsinvolved
inmotivationandaddiction.
ROLESOFPERIAQUEDUCTALGRAY&BRAINSTEM
Anothersiteofactionformorphineandendogenousopioidpeptidesisthemesencephalicperiaqueductal
gray(PAG).AninjectionofopioidsintothePAGinducesanalgesia.ThePAGisapartofadescending
pathwaythatmodulatespaintransmissionbyinhibitionofprimaryafferenttransmissioninthedorsalhorn
(Figure86).ThesePAGneuronsprojectdirectlytoandactivatetwogroupsofneuronsinthebrainstem:
serotonergicneuronsinthenucleusraphemagnusandcatecholaminergicneuronsintherostral
ventromedialmedulla.Neuronsinbothoftheseregionsprojecttothedorsalhornofthespinalcordwhere
thereleasedserotoninandnorepinephrineinhibittheactivityofdorsalhornneuronsthatreceiveinputfrom
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nociceptiveafferentfibers(Figure86).Thisinhibitionoccurs,atleastinpart,duetotheactivationofthe
dorsalhornenkephalincontaininginterneurons.Thereisalsoagroupofbrainstemcatecholaminergicneurons
inthelocuscoeruleusthatareelementsofthisdescendingpainmodulatingpathway.Thesepontineneurons
alsoexerttheiranalgesiceffectbythereleaseofnorepinephrineinthedorsalhorn.
Theanalgesiceffectofelectroacupuncturemayinvolvethereleaseofendogenousopioidsandactivationof
thisdescendingpainmodulatorypathway.Electroacupunctureactivatesascendingsensorypathwaysthatemit
collateralsinthePAGandinthebrainstemserotonergicandcatecholaminergicregions.Theanalgesiceffect
ofelectroacupunctureispreventedbyadministrationofnaloxone,anopioidreceptorantagonist.
CLINICALBOX86Motivation&Addiction
Neuronsintheforebrainventraltegmentalareaandnucleusaccumbensareinvolvedinmotivatedbehaviors
suchasreward,laughter,pleasure,addiction,andfear.Theseareashavebeenreferredtoasthebrainsreward
centerorpleasurecenter.Themesocorticaldopaminergicneuronsthatprojectfromthemidbraintothe
nucleusaccumbensandthefrontalcortexarealsoinvolved.Addiction,definedastherepeatedcompulsive
useofasubstancedespitenegativehealthconsequences,canbeproducedbyavarietyofdifferentdrugs.
AccordingtotheWorldHealthOrganization,over76millionpeopleworldwidesufferfromalcoholabuse,and
over15millionsufferfromdrugabuse.Notsurprisingly,alcoholanddrugaddictionareassociatedwiththe
rewardsystem.Thebeststudiedaddictivedrugsareopioids(eg,morphineandheroin)othersincludecocaine,
amphetamine,alcohol,cannabinoids,andnicotine.Thesedrugsaffectthebrainindifferentways,butallhave
incommonthefactthattheyincreasetheamountofdopamineavailabletoactonD3receptorsinthenucleus
accumbens.Thus,acutelytheystimulatetherewardsystemofthebrain.Longtermaddictioninvolvesthe
developmentoftolerance,whichistheneedforincreasingamountsofadrugtoproduceahigh.Also,
withdrawalproducespsychologicalandphysicalsymptoms.Oneofthecharacteristicsofaddictionisthe
tendencyofaddictstorelapseaftertreatment.Foropioidaddicts,therelapserateinthefirstyearisabout80%.
Relapseoftenoccursonexposuretosights,sounds,andsituationsthatwerepreviouslyassociatedwithdrug
use.Evenasingledoseofanaddictivedrugfacilitatesreleaseofexcitatoryneurotransmittersinbrainareas
concernedwithmemory.Themedialfrontalcortex,hippocampus,andamygdalaareconcernedwithmemory,
andtheyallprojectviaexcitatoryglutamatergicpathwaystothenucleusaccumbens.Despiteintensivestudy,
relativelylittleisknownaboutthebrainmechanismsthatcausetoleranceanddependence.However,thetwo
canbeseparated.Absenceofarrestin2blockstolerancebuthasnoeffectondependence.Arrestin2isa
memberofafamilyofproteinsthatinhibitheterotrimericGproteinsbyphosphorylatingthem.
THERAPEUTICHIGHLIGHTS
Withdrawalsymptomsandcravingsassociatedwithaddictiontoopioidscanbereversedbytreatmentwith
variousdrugsthatactonthesameCNSreceptorsasmorphineandheroin.Theseincludemethadoneand
buprenorphine.TheUSFederalDrugAdministrationhasapprovedtheuseofthreedrugsfortreatmentof
alcoholabuse:naltrexone,acamprosate,anddisulfiram.Naltrexoneisanopioidreceptorantagonistthat
blockstherewardsystemandthecravingforalcohol.Acamprosatemayreducethewithdrawaleffects
associatedwithalcoholabuse.Disulfiramcausesanaccumulationofacetaldehydebypreventingthefull
degradationofalcohol.Thisleadstoanunpleasantreactiontoalcoholingestion(eg,flushing,nausea,and
palpitations).Topiramate,aNa+ channelblocker,isshowingpromiseinclinicaltrialsofalcoholaddiction.
Thisisthesamedrugthathasshowntobeeffectiveintreatmentofmigraineheadaches.
STRESSINDUCEDANALGESIA
Itiswellknownthatsoldierswoundedintheheatofbattleoftenfeelnopainuntilthebattleisover.Thisisan
exampleofstressinducedanalgesiathatcanalsobeexemplifiedbyreducedpainsensitivitywhenbeing
attackedbyapredatororotherstressfulevents.Releaseofnorepinephrine,perhapsfrombrainstem
catecholaminergicneurons,intheamygdalamaycontributetothisphenomenon.Asdescribedabove,the
amygdalaisapartofthelimbicsystemthatisinvolvedinmediatingthemotivationalaffectiveresponsesto
pain.
Thereleaseofendogenouscannabinoidssuchas2arachidonoylglycerol(2AG)andanandamidemayalso
contributetostressinducedanalgesia.ThesechemicalscanactonatleasttwotypesofGproteincoupled
receptors(CB1andCB2).CB1receptorsarelocatedinmanybrainregions,andactivationofthesereceptors
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accountsfortheeuphoricactionsofcannabinoids.CB2receptorsareexpressedinactivatedmicrogliaunder
variouspathologiesthatareassociatedwithchronicneuropathicpain(seeClinicalBox83).Bindingofan
agonisttoCB2receptorsonmicrogliareducestheinflammatoryresponseandhasananalgesiceffect.Workis
underwaytodevelopselectiveCB2agonistsfortherapeutictreatmentofneuropathicpain.

CHAPTERSUMMARY
Touchandpressurearesensedbyfourtypesofmechanoreceptorsthatareinnervatedbyrapidly
conductingAandAsensoryafferents.TheyarerapidlyadaptingMeissnercorpuscles(respondto
changesintextureandslowvibrations),slowlyadaptingMerkelcells(respondtosustainedpressureand
touch),slowlyadaptingRuffinicorpuscles(respondtosustainedpressure),andrapidlyadapting
Paciniancorpuscles(respondtodeeppressureandfastvibrations).
NociceptorsandthermoreceptorsarefreenerveendingsonunmyelinatedCfibersorlightlymyelinated
Afibersinhairyandglaborousskinanddeeptissues.Thesenerveendingshavevarioustypesof
receptorsthatareactivatedbynoxiouschemical(eg,TRPV1andASIC),mechanical(eg,P2X,P2Yand
TRPA1),andthermal(eg,TRPV1)stimuli.Inaddition,chemicalmediators(eg,bradykinin,
prostaglandin,serotonin,andhistamine)releasedinresponsetotissueinjurydirectlyactivateor
sensitizenociceptors.
Thegeneratororreceptorpotentialisthenonpropagateddepolarizingpotentialrecordedinasensory
organafteranadequatestimulusisapplied.Asthestimulusisincreased,themagnitudeofthereceptor
potentialisalsoincreased.Whenitreachesacriticalthreshold,anactionpotentialisgeneratedinthe
sensorynerve.
Convertingareceptorstimulustoarecognizablesensationistermedsensorycoding.Allsensory
systemscodeforfourelementaryattributesofastimulus:modality,location,intensity,andduration.
Painisanunpleasantsensoryandemotionalexperienceassociatedwithactualorpotentialtissue
damage,ordescribedintermsofsuchdamage,whereasnociceptionistheunconsciousactivityinduced
byaharmfulstimulusappliedtosensereceptors.FirstpainismediatedbyAfibersandcausesasharp,
localizedsensation.SecondpainismediatedbyCfibersandcausesadull,intense,diffuse,and
unpleasantfeeling.Acutepainhasasuddenonset,recedesduringthehealingprocess,andservesasan
importantprotectivemechanism.Chronicpainispersistentandcausedbynervedamageitisoften
associatedwithhyperalgesia(anexaggeratedresponsetoanoxiousstimulus)andallodynia(asensation
ofpaininresponsetoaninnocuousstimulus).ChronicpainisoftenrefractorytoNSAIDsandopioids.
Visceralpainispoorlylocalized,unpleasant,andassociatedwithnauseaandautonomicsymptoms.It
oftenradiates(orisreferred)toothersomaticstructuresperhapsduetoconvergenceofsomaticand
visceralnociceptiveafferentfibersonthesamesecondorderneuronsinthespinaldorsalhornthat
projecttothethalamusandthentotheprimarysomatosensorycortex.
Discriminativetouch,proprioception,andvibratorysensationsarerelayedviathedorsalcolumn(medial
lemniscus)pathwaytotheVPLinthethalamusandthentotheprimarysomatosensorycortex.Painand
temperaturesensationsaremediatedviatheventrolateralspinothalamictract,whichprojectstotheVPL
andthentocortex.Thediscriminativeaspectofpainresultsfromactivationoftheprimary
somatosensorycortexthemotivationalaffectivecomponentofpainisfromactivationofthefrontal
lobe,limbicsystem,andinsularcortex.
TransmissioninpainpathwaysismodulatedbyendogenousopioidsthatcanactinthePAG,brainstem,
spinalcord,anddorsalrootganglia.DescendingpainmodulatingpathwaysincludeneuronsinthePAG,
nucleusraphemagnus,rostralventromedialmedulla,andlocuscoeruleus.
Newpaintherapiesfocusonsynaptictransmissioninnociceptionandperipheralsensorytransduction.
CapsaicintransdermalpatchesorcreamsreducepainbyexhaustingthesupplyofsubstancePinnerves
andbyactingonTRPV1receptorsintheskin.Lidocaineandmexiletineareusefulinsomecasesof
chronicpainandactbyblockingNav1.8,whichisuniquelyassociatedwithnociceptiveneuronsin
dorsalrootganglia.Ziconotide,avoltagegatedNtypeCa2+ channelblocker,isusedforintrathecal
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analgesiainpatientswithrefractorychronicpain.Gabapentin,ananticonvulsantdrug,iseffectivein
treatmentofneuropathicandinflammatorypainbyactingonvoltagegatedCa2+ channels.Topiramate,
aNa+ channelblocker,isanotheranticonvulsantdrugthatcanbeusedtotreatmigraines.NMDA
receptorantagonistscanbecoadministeredwithanopioidtoreducetolerancetoanopioid.

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