Peptide and Lipid Modulation of Glutamatergic Afferent Synaptic Transmission in the Solitary Tract Nucleus.

0.55 MB·English

by  Andresen, Michael C.

REVIEWARTICLE
published:10January2013
doi:10.3389/fnins.2012.00191
Peptide and lipid modulation of glutamatergic afferent
synaptic transmission in the solitary tract nucleus
MichaelC.Andresen*,JessicaA.Fawley andMackenzieE.Hofmann
DepartmentofPhysiologyandPharmacology,OregonHealthandScienceUniversity,Portland,OR,USA
Editedby: The brainstem nucleus of the solitary tract (NTS) holds the first central neurons in major
KevinW.Williams,TheUniversityof homeostatic reflex pathways.These homeostatic reflexes regulate and coordinate multi-
TexasSouthwesternMedicalCenter,
pleorgansystemsfromgastrointestinaltocardiopulmonaryfunctions.Thecoreofmanyof
USA
thesepathwaysarisefromcranialvisceralafferentneuronsthatenterthebrainasthesoli-
Reviewedby:
KazuhiroNakamura,KyotoUniversity, tarytract(ST)withmorethantwo-thirdsarisingfromthegastrointestinalsystem.Aboutone
Japan quarterofSTafferentshavemyelinatedaxonsbutthemajorityareclassedasunmyelinated
BretN.Smith,UniversityofKentucky C-fibers.AllSTafferentsreleasethefastneurotransmitterglutamatewithremarkablysimi-
CollegeofMedicine,USA
lar,high-probabilityreleasecharacteristics.SecondorderNTSneuronsreceivesurprisingly
*Correspondence:
limitedprimaryafferentinformationwithoneortwoindividualinputsconvergingonsingle
MichaelC.Andresen,Departmentof
PhysiologyandPharmacology, secondorderNTSneurons.A-andC-fiberafferentsnevermixatNTSsecondorderneurons.
OregonHealthandScience Manytransmittersmodifythebasicglutamatergicexcitatorypostsynapticcurrentoftenby
University,3181SWSamJackson reducing glutamate release or interrupting terminal depolarization.Thus, a distinguishing
ParkRoad,Portland,OR,USA.
feature of ST transmission is presynaptic expression of G-protein coupled receptors for
e-mail:[email protected]
peptides common to peripheral or forebrain (e.g., hypothalamus) neuron sources. Presy-
napticreceptorsforangiotensin(AT1),vasopressin(V1a),oxytocin,opioid(MOR),ghrelin
(GHSR1),andcholecystokinindifferentiallycontrolglutamatereleaseonparticularsubsets
ofneuronswithmostotherSTafferentsunaffected.Lastly,lipid-likesignalsaretransduced
bytwokeySTpresynapticreceptors,thetransientreceptorpotentialvanilloidtype1and
the cannabinoid receptor that oppositely control glutamate release. Increasing evidence
suggests that peripheral nervous signaling mechanisms are repurposed at central termi-
nalstocontrolexcitationandaremajorsitesofsignalintegrationofperipheralandcentral
inputsparticularlyfromthehypothalamus.
Keywords:solitarytractnucleus,neuropeptides,capsaicin,TRPV1,vagalafferents
Thenervoussystemmakesauniquecontributiontotheregula- For example, chronic aerobic fitness training often restructures
tory mechanisms that help to preserve homeostatic integrity in the heart so that the resting stroke volume is increased but this
the face of constantly changing demands. The central nervous new state requires complementary changes in neural regulation
system (CNS) serves as a key integrator and coordinator across aroundanew,lowerrestingheartrate(Jacksonetal.,2005;Higa-
multiple organ systems and tissues. The CNS and its peripheral Taniguchi et al., 2009; Cavalleri et al., 2011). All circumstances
neural partners are not only capable of rapidly responding over requirehomeostaticallysimilaroutcomesthatprovideaconsistent
greatdistancestocoordinateorganfunctionbuttheyalsohavethe cellularmilieuofbloodgases,nutrients,andwasteremoval.How-
capacity to remodel chronically. By orchestrating visceral organ ever,frankdysregulationincreasinglyisrecognizedasanintegral
functions,the CNS helps to foster effective system-wide control partof pathologicalstatessuchasmetabolicsyndromeinwhich
overtheconditionsmaintainingcellularhomeostasis.Thehome- multiplesystemsbecomecompromisedorevenfail(Albertietal.,
ostaticpalateofregulated“states”spansvitalenergy,temperature, 2005,2006;Perez-Tilveetal.,2006).Theaimof thereviewisto
ionic,andmetabolicstatus(Schwartzetal.,2000;Nakamuraand focusonthebuildingblocksofneuralsynaptictransmissionthat
Morrison,2008;Dallman,2010;GrillandHayes,2012).Organism- determineandmodifytheperformanceoftheseneuralpathways.
widebalancematchescriticalprocessesmediatingenvironmental One fundamental aspect essential to understanding homeo-
exchange (at the skin, lung, and gastrointestinal tract) with the static and pathologic complexities is an appreciation of normal
appropriate transportation (cardiorespiratory and gastrointesti- regulationandtheframeworkandstructureofinteractionsacross
nal).Theregulatorychallenge,ofcourse,isdynamicinthatacute organsystems.Thegoalof thischapteristofocusontheneural
changesinorganconditionsrequirespeedyadjustmentsbutlong signalinginterfacebetweenincominginformationaboutvisceral
term,chronicchangesrequirethecapacitytoadapttosustained statusandtheinitiationof CNSregulatoryresponses.Fororgan
changes.Eveninnormalphysiologicalcircumstances,anewstate regulation,thisafferent-CNSinterconnectionoccurslargelyatthe
can require adjustments in the performance characteristics of caudalthirdofthenucleusofthesolitarytract(NTS).TheNTSisa
neuralcontrolpathwaystoaccommodatethesenormalchanges. majorgatewayforcranialvisceralafferentinformation(Andresen
www.frontiersin.org January2013|Volume6|Article191|1
Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
and Kunze, 1994; Andresen and Paton, 2011) and, as such, is a NTSsubregionsandsomesynapticterminalsfromvagalafferents
uniquefocusofvisceralorganinformationintheCNS.Thisreview directlycontactDMNcellprocesses(Rinamanetal.,1989).
summarizesthefundamentalbuildingblocksfortheprocessingof
afferentsignalsattheNTSaspartofoverallintegrationandillus- AFFERENTCONNECTIONSATNTS
tratesthatinformationprocessingatthissitegoeswellbeyonda The physical wiring pathways for neural regulation begin with
simple relay and broadcast of visceral signals. Recent work sug- thevisceralprimaryafferentsofcranialnervesandtheirphysical
gests that, across multiple organ systems, all circuits involving contacts on NTS second order sensory neurons (Andresen and
the NTS appear to utilize similar basic communication mecha- Kunze,1994;Craig,2002;Andresen and Paton,2011). However,
nisms–mechanismsincommon.Incontrast,however,otheraspects inmostvitalorgans,visceralsensoryprimaryafferentsarisefrom
offermechanismsofdistinctionsuchasligand-gatedionchannels dual sources.Cranialvisceralafferentshavecellbodieschieflyin
andG-proteincoupledreceptor(GPCR)-basedsystemsthatmay thenodoseandpetrosalgangliaandsendtheirafferentaxonsinto
distinguishparticularpathways. theNTS.Asecondafferentsourcearisesfromspinalvisceralaffer-
entswhichhavecellbodieslocatedinthedorsalrootgangliabut
INDISTINCTNEIGHBORHOODS their axons enter the CNS at the spinal cord dorsal horn. Both
Overall, the NTS is quite diverse. Structurally, the NTS has cranial and spinal visceral sensory neurons include myelinated
regions distinguished cytoarchitecturally by morphological fea- (mostlyAδ)andunmyelinatedsubtypesand,formostorgans,the
tures(LoewyandBurton,1978;KaliaandSullivan,1982).How- slowlyconductingC-typeafferentsgreatlyoutnumberthemyeli-
ever, the distribution of cranial visceral afferent axons and ter- nated class of afferents by 8–10-fold regardless of their cranial
minations poorly conform to this cytoarchitectural topography, orspinaldestination(Agostonietal.,1957;Andresenetal.,1978;
particularly rostro-caudally. Thus,despite input fibers that arise Sant’Ambrogio,1987;KubinandDavies,1995).Thiscranialinfor-
fromdistinctlydifferentvisceralorgans(e.g.,gastrointestinalsys- mationflowsmostlythroughtheIXthandXthcranialnervesto
tem,heart,bloodvessels,lung,orairways),thesevariousafferents formthefirststepofpathwayswhicharelargelyconcentratedinthe
distributebroadlywithinNTSandareindistinctinlocationand brainstem.Thesebrainstempathwayshaveastructurethatfeeds
morphology.Thisdiversityandambiguityofdistributionextends backtoregulatetheorgansfromwhichthoseafferentsoriginated.
to neurochemical phenotypes of NTS neurons – glutamatergic, Spinal visceral primary afferents often follow sympathetic nerve
γamino-butyricacid(GABA)synthesizing,catecholamine(CA) trunks to reach their cell bodies within the dorsal root ganglia.
synthesizing,pro-opiomelanocortin (POMC),and other unique Thisspinalinformationmaycontributetonociceptivesignaling
neurons(AndresenandKunze,1994;Andresenetal.,2007a;Wan withinthespinalcordandlessdirectlyinfluencesvisceralorgan
et al., 2008). One early idea held that particular afferent inputs regulation (Foreman, 1999, 2000; Gamboa-Esteves et al., 2001).
mightspecificallycontacthistologicallydefinedsubnucleiwithin Thesynapsesfromcranialvisceralprimaryafferentsdefinesecond
thecaudalNTS(KaliaandMesulam,1980).Acrossstudieshow- orderafferentneuronswithintheNTS,butthefinalprojections
ever,multiplemethodsoftracingmarkersofcranialafferentsfrom of theaxonsof mostsecondorderNTSneuronsarelesscertain.
visceralorganstotheirdestinationsintheNTSproduced“cloud”- Infact,itisquitelikelythatmanysecondorderNTSneuronshave
likemapsthatcrossedmorphologicalsubregionsand,inaddition, multi-functionalaxonarchitecturesinwhichbranchesfromsin-
functional approaches using physiological activation generated gleneuronsservelocalinterneuronfunctionsandotherbranches
regional overlays that were similarly indistinct (Andresen and projecttotargetsoutsideoftheNTS.Manyofthesepathwaysmay
Paton, 2011). Thus, cardiovascular investigators produced dia- be relatively inactive under normal circumstances since C-fiber
grams representing locations of NTS neurons involved in car- afferent have high thresholds for sensory activation and do not
diovascular regulation (Ciriello and Calaresu, 1981; Donoghue contributetorestingcontrolinautonomicregulationandsatiety
et al., 1981b; Chan and Sawchenko, 1998; Corbett et al., 2005). (Aarsetal.,1978;Ritter,2004).
Respiratory (Kubin et al., 1991; Haxhiu and Loewy, 1996) or
gastrointestinal(Altschuleretal.,1991;Babicetal.,2009)inves- LIMITEDAFFERENTCONVERGENCE
tigatorsalsodiagrammedassociatedfunctionalzones.Theresults Earlyworkestablishedthatcranialvisceralafferentresponsiveneu-
ofthesetargeteddistributions,however,areremarkablysimilarto ronswerelocatedincommonsubregionswithintheNTS.Given
eachother,andtheresemblancesuggeststhattheseafferent-linked thecloseproximityofdifferentafferentterminals,akeyquestion
functionalregionslargelyoverlapandcorrespondtoanatomicsub waswhetherafferentinformationfrommultipleorgansimpinged
regions with fuzzy boundaries and co-mingled neurons of dif- onsingleNTSneurons.Thecervicalvagusnervecontainsmostly
ferent functions. Such global maps are further confounded by a afferentaxons.Despiteits>10,000cranialvisceralafferentsaxons,
commoncellularfeatureofNTSneurons–thedendritesofindi- maximalelectricalactivationofthevagaltrunkgenerallytriggered
vidualNTSneuronsextendtoreachacrossconsiderabledistances responsesconsistentwithasingleinputactivatingNTSneurons
(Deucharsetal.,2000;Patonetal.,2000;Kubinetal.,2006).Thus, (Agostonietal.,1957).Multipleassessmentsof thepotentialfor
thesynapticlocaleofsingleneuronsisambiguousandoftenbest convergenceofafferentsfromseparatenervesontosingleneurons
attributedtomultipleanatomicalsubnuclei.Thisaspectofcellular suggested that <15% of individual NTS neurons have multiple
anatomyfurtherblursthespatialboundariesforfunctionalgroups afferentinputs(Donoghueetal.,1981b,1985;Paton,1998).Even
(e.g.,baroreceptivevs.gastrointestinalregions)aspharmacolog- underintensestimulation,arterialbaroreceptoractivationdidnot
ical targets. Lastly, important motor neurons within the dorsal trigger responses by converging onto NTS neurons activated by
motornucleus(DMN)spreaddendritesintoanatomicallydefined cardiacafferents(Silva-Carvalhoetal.,1998;Seagardetal.,1999).
FrontiersinNeuroscience|NeuroendocrineScience January2013|Volume6|Article191|2
Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
Testsinunitrecordingswithmultipleconverginginputsshowed The counterbalance to excitation lies largely in the GABAer-
thattheadditionalinputsarrivedviapolysynapticpaths–thatis, gic neurons that are interspersed throughout the NTS (Izzo
indirectrelaysratherthandirectterminationsofmultipledifferent etal.,1992;ChanandSawchenko,1998;StornettaandGuyenet,
afferentsonsinglesecondorderNTSneurons(ZhangandMifflin, 1999; Fong et al., 2005) that express the key isoforms of syn-
1995;Mifflin,1996).Anotherremarkablefeatureof convergence thetic enzymes, glutamate decarboxylases (GAD), GAD65 and
isthatafferentinputsaresegregatedbytheiraxonfibertype.NTS GAD67. GABAergic NTS neurons play well-established,specific
neuronsreceivingC-fiberinputsdonotalsodirectlyreceivemyeli- roles in respiratory and gastrointestinal regulation. In respira-
natedafferentinputs(Donoghueetal.,1981a;Doyleetal.,2002; tion,GABAergicpumpcellsaresecondorderNTSneuronswhich
Jin et al.,2004b;Andresen and Peters,2008).As outlined below projectfromNTStotheventrolateralmedullaandtheponsbut
oneofthekeyphenotypicmarkersfortheunmyelinatedafferent these also serve as local interneurons via recurrent collaterals
axonsistheTransientreceptorpotentialvanilloidtype1(TRPV1). within the commissural nucleus to inhibit other second order
TRPV1+afferentsdonotmixwithTRPV1−afferentsatmedial NTSneuronsthatreceiverapidlyadaptingstretchreceptorinputs
NTSneuronssothatTRPV1afferentsare–amechanismofdistinc- (Daviesetal.,1987;EzureandTanaka,1996;Kubinetal.,2006).
tion(Petersetal.,2010,2011;Shoudaietal.,2010)andwethuswill Forgastrointestinalpathways,GABAergicinhibitoryNTSneurons
refertothereceivingNTSneuronsasTRPV1+.Overlappingglobal tonicallyinhibittheDMNof thevagus(BrowningandTravagli,
afferentdistributionmapsdispeltheearliestnotionsofdedicated 2010).Regardlessofthefunctionalpathway,GABAergicNTSneu-
physicallocalitiesascentersofdedicatedfunctionandinsteadsug- rons are nearly exclusively second order neurons (Glatzer et al.,
gestthatthereisaclosephysicalproximityofverydifferentafferent 2007; Bailey et al., 2008) and 70% receive a single cranial vis-
circuits destined to regulate very different functions (e.g., gas- ceralafferent(Baileyetal.,2008).However,thedensityofGABA
trointestinaladjacenttoairwayafferentreceivingneurons).Atthe releasingcontactsfromsingleaxonsisquitelimitedatNTSneu-
levelofindividualneurons,theresultsdemonstratehighlyfocused rons(McDougallandAndresen,2012).Sustainedvisceralafferent
organizationof pathwaysthattravelnearbybutareseparatedby stimulation activated Fos expression in substantial numbers of
discrete synaptic connections – a mechanism of distinction. This GABAergicneuronsinvivo(ChanandSawchenko,1998;Weston
separationimportantlypreservesfunctionallyseparatebutparal- et al.,2003). Not surprisingly,blockade of GABAergic signaling
lelneuralpathways.Recognitionofthesefundamentalstructural intheNTSbroadlyimpactedcardiovascular,respiratory,andgas-
features may guide our understanding of the basic mechanisms trointestinalregulation(AndresenandMendelowitz,1996;Kubin
thatunderlietheneuralregulationofvisceralorgansandmayhelp etal.,2006;Travaglietal.,2006;Kenny,2011).
optimizetherapeuticapproachesduringongoingdysregulationor Although GABA is an important neurochemical phenotype,
pathology. substantialnumbersofNTSneuronsfeatureuniqueneurochem-
ical phenotypes that represent smaller, diverse sub populations.
NTSCELLULARDIVERSITYACROSSCIRCUITROLES Forexample,20–35%oftheNTSneuronsinthecaudal-postremal
Iftheafferent-NTSinterfaceisrelativelysimplebutisolatedfrom regionexpressthekeyCAsyntheticenzymetyrosinehydroxylase
others, what features distinguish different functional pathways? (Austgen et al., 2009). A subset of CA-NTS neurons (10–20%)
The NTS is well known for its phenotypic diversity. One major maybedevotedtocardiovascularregulation(Korner,2007).CA
difference is reflected in the neurotransmitter synthesis capacity neurons were the focus of considerable work in the early 1960s
or neurochemical characteristics of these neurons – a form of (Dahlstrom and Fuxe, 1964) as members of “slow neurotrans-
cellular phenotype. The neurotransmitters themselves of course mitter” neurons hypothesized to be key to long term regula-
areonemajorcellulardifference.Atthebasicsof signaling,cen- tory processes (Korner, 2007). CA-NTS neurons consist of A
2
tralreflexcircuitsconstantlybalanceexcitationwithinhibitionin noradrenergicneuronsandC adrenergicneuronsandCA-NTS
2
propagatingsignalsthroughnetworks(SabatiniandRegehr,1999; neurons were among the first central CA neurons recognized
Abbott and Regehr, 2004; Semyanov et al., 2004). As elsewhere (Dahlstrom and Fuxe, 1964). The A /C groups of NTS neu-
2 2
intheCNS,excitationreliesmostimportantlyonglutamateasa ronsbroadlyimpacthomeostaticregulation(Hollisetal.,2004)
neurotransmitterwhiletheprimaryinhibitoryneurotransmitter includingcardiovascular,respiratory,andgastrointestinalsystems
isGABA. (AndresenandKunze,1994;Saper,2002).Variousafferentstimuli
Therelayofexcitationfromcranialvisceralafferentsrequires activateCA-NTSneuronswhichthenprojectextensivelytoareas
NTS neurons of an excitatory neurochemical phenotype. The includingthehypothalamus,amygdala,nucleusaccumbens,and
evidence for excitatory glutamate includes the expression of the DMN of the vagus (Riche et al.,1990; Travagli et al.,2006). C
2
vesicularglutamatetransporterinNTSneuronsincludingvGlut2 neuronshavemarkedlyheterogeneousresponses(ChanandSaw-
as part of their neurochemical profile (Stornetta et al., 2002; chenko,1994)andsomerequireratherintenseafferentchallenges
Moechars et al., 2006; Affleck et al., 2012). A selective knock- toproduceactivationof FOSexpression(ChanandSawchenko,
out of vGlut2 is perinatal lethal with suggestions of respiratory 1998),circumstancesreminiscentofC-fiberrecruitment.Unlikein
failureandsuchearlyfatalityisconsistentwithanabsoluterequire- manyotherareasoftheCNS,CA-NTSneuronsdonotsynthesize
ment for this key glutamatergic mechanism (Moechars et al., GABA(StornettaandGuyenet,1999).
2006). NTS projection neurons convey afferent information to
key targets beyond NTS including the paraventricular nucleus PEPTIDERGICSIGNALINGINNTS
of thehypothalamus(PVN)viaglutamaterelease(Afflecketal., Although much of the signaling within the NTS utilizes release
2012). ofaminoacidorbiogenicaminesastransmitters(Andresenand
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Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
Kunze,1994;Jordan,2005;Kubinetal.,2006),thebroadimpact earlyattentiontothepresenceofCAneuronswithintheNTS,the
ofpeptideneurotransmittersisunmistakablewithmorethantwo mechanismsofpeptideaction,andinteractionremainimprecisely
dozenpeptidesand/ortheirreceptorslongimplicated(Lawrence known.
andJarrott,1996;Zhuoetal.,1997;Chaudhrietal.,2008;Michelini Glucagon-likepeptide-1(GLP-1)isincreasinglyrecognizedas
and Stern,2009). Peptides offer another layer of signal integra- animportantsignalingpartnermoleculethatispresentperipher-
tionsincetheirreceptorsoftentargetionchannels,frequentlyare allyaswellasintheNTS.GLP-1isreleasedfromboththegastroin-
presynaptic on afferent terminals and affect the release of other testinal tract and from a limited population of preproglucagon
neurotransmitters. The µ-opiate receptor is particularly wide- (PPG)NTSneurons(Larsenetal.,1997).GLP-1affectsenergybal-
spread in the NTS (Dashwood et al.,1988). Far more restricted ance(lowersbloodglucoseandstimulatesinsulinsecretion)and
examplesarevasopressin(AVP;Baileyetal.,2006b)andoxytocin influencesthermogenesis,hunger,andsatiety(Kenny,2011).PPG
(OT;Petersetal.,2008)receptorswhicharestronglylinkedtothe neuroncellbodiesarelocatedinthecaudalNTSadjacenttoarea
hypothalamus. These two peptide receptors oppositely regulate postrema(Llewellyn-Smithetal.,2011).GLP-1receptorblockade
thereleaseofglutamatefromsolitarytract(ST)afferentterminals increases food intake (Alhadeff et al.,2012). Despite this strong
(OTfacilitatesreleaseandAVPinhibitsrelease)onlimitednum- connectiontofeedingbehaviorsandthemesolimbicrewardsys-
bersofneuronswithintheNTS.Thesereceptorstohypothalamic tem,injectionsoftheGLP-1analogexendin-4alsoincreasesheart
neuropeptides represent one of the most common schemes for rateandbloodpressurewhendeliveredperipherallyorcentrally
differentialpathwaycontrolofNTSneurons.Inthehypothalamic withsubstantialevidenceforactivationofTHneuronswithinthe
pattern,AVPorOTreceptorsresidepresynapticallyondifferent NTSandelsewhere(Yamamotoetal.,2002).Activationof GLP-
sets of cranial afferent terminals and have been linked to plas- 1inmanypancreas-projectingvagalmotoneuronsevokesaction
ticchangesbroughtonbyexerciseconditioningthatchangesthe potentialsandisimplicatedastargetingpotassiumandGABAer-
reflexperformanceinspecificpathwaysthroughNTS(Michelini giccurrents(Wanetal.,2007).Onerelativelyrarerbutimportant
andMorris,1999;Michelini,2007;MicheliniandStern,2009;Stern neurochemical phenotypes of NTS neurons is the POMC neu-
et al., 2012). Another peptide, angiotensin, facilitates glutamate ron group linked to feeding behavior (Appleyard et al., 2005;
releasefromSTafferentterminalsactingthroughAT1receptors Kenny,2011). Mutated forms of the POMC and melanocortin-
(Barnes et al., 2003) but is much more widespread including 4 receptor genes are associated with severe, early onset obesity
postsynapticNTSneuronmembranesbutalsopresynapticallyat (Clement et al., 2002). The POMC NTS neurons together with
symmetricsynapsesthatarepresumablyGABAergic(Huangetal., POMC neurons within the arcuate nucleus of the hypothala-
2003). mus help to regulate energy homeostasis through widespread
CA-NTS neurons contain subsets of peptide receptors for limbic,motor,andautonomicprojectionsandaremodulatedby
cholecystokinin(CCK),ghrelin,andopioids,apatternfoundin appetite-regulatinghormonessuchasleptinandglucose(Spiegel-
otherNTSneuronsubsets,andthesepeptidesmodifythebehavior manandFlier,2001;Cone,2005;Rotheretal.,2008;Grill,2010;
ofspecificpathways.Thus,peptideneurotransmissionappearsto Mountjoy,2010;Kenny,2011).POMCNTSneuronswerewidely
bekeymechanismofdifferentialcontrol.Glutamatereleaseonto dispersed but CCK activated FOS expression in a dose graded
CA-NTSneuronswithingastrointestinalpathwaysismodifiedby fashion (Appleyard et al., 2005). POMC NTS neurons received
peptides acting presynaptically on ST afferents to modify trans- direct ST excitatory inputs which were often facilitated by CCK
mission and manage pathway outcomes (Appleyard et al.,2007; orinhibitedbymet-enkephalin,bothpresynapticactions.Given
Cui et al., 2011, 2012a). Ghrelin and opioids strongly inhibited the gastrointestinal focus of much of this work, it is less clear
thepresynapticprocessofreleaseofafferentglutamateontomany whetherthesepeptidesignalsalsomayberepresentedinthesig-
CA-NTSneurons(Cuietal.,2011,2012a).AlthoughCA-NTSneu- naling of other neighboring pathways such as cardiorespiratory
ronsoftenreceivedmultiplecranialafferentinputs,itisnotclear control.
whethertheserepresentdifferent,convergingsensorymodalities, A recurring theme in peptide signaling is the discovery of a
i.e., mixed modality inputs or simply multiple similar ST affer- peptide through its actions on a peripheral end organ followed
ents;Appleyardet al.,2007). The STafferent inputsto CA-NTS by evidence for the same peptide within the CNS including the
neuronswereoftenCCKsensitiveandthesesecondorderneurons NTS(Chaudhrietal.,2008;Simpsonetal.,2012).Suchdualrep-
hadprominentexpressionofA-typepotassiumcurrentsthatsup- resentationatdisparatesites(e.g.,opioids,somatostatin,orCCK)
pressedactionpotentialgenerationinatimedependentfashion has generated substantial discussion about whether peripherally
andthusprovidedpostsynapticattenuationofafferenttransmis- released peptides influence reflex control solely via peripheral
sion(Appleyardetal.,2007).Themulti-systemaspectofCA-NTS actionsonprimaryafferentsorwhetherthosepeptidesmightpen-
neurons may offer targets in common that reach across other- etrate the CNS (Herbert and Saper,1990;Baptista et al.,2005b,
wisefunctionallydiscretepathwaystoalterchronichomeostatic, 2007). Similar discussions arise concerning peptides with the
behavioral, or metabolic states during obesity, hypertension, or potentialfordualdeliverymechanisms–hormonalsecretioninto
stress(Kenny,2011).Co-localizationofmorethanoneneuropep- thebloodstreamorneuralsignalsdeliveredthroughspecificfiber
tide receptor as well as localization at pre- and/or postsynaptic contacts.With respect to the caudal NTS,the local blood–brain
elements may differentiate control of information to particular barrierisrelativelyporousviafenestratedvascularendothelialcells
targets and increases the combinations for signal crosstalk, e.g., (Grossetal.,1990,1991;BroadwellandSofroniew,1993;Huang
betweenopioidsandCAs(Sumaletal.,1983;Pickeletal.,1989; etal.,2003).Theimportantimplicationsdemandquitechalleng-
Velleyetal.,1991;Nirenbergetal.,1995).Thusdespiterelatively ing,additionalcomprehensiveworktoresolvethesemechanisms,
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Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
especially with regard to pathway performance changes during MECHANISMINCOMMON–SYNCHRONOUSGLUTAMATE
pathophysiologicalstates. TRANSMISSION
A-andC-typeprimaryafferentshavesubstantiallydifferentaction
potentialsandbiophysicalexcitability(Schildetal.,1994;Schild
DESTINATIONS
andKunze,2012).Centrally,actionpotentialsactivatefastsynap-
Cellular themes of neurotransmission appear to be commonly
tictransmissionbytriggeringvoltage-activatedcalciumchannels.
repeatedacrossdifferentneurochemicalphenotypesofNTSsec-
Thiscalciumentrymediatesfast,synchronizedfusionofglutamate
ond order neurons. The nature of the functional outcome of
vesicles.Despitecharacteristicdifferencesinafferentexcitability,
actionsatNTSneurons,however,willbedeterminedbythedes-
fast glutamate transmission is remarkably uniform across all ST
tinationof itsaxon.Anterogradeandretrogradelabelingstudies
afferents (Bailey et al.,2006b;Andresen and Peters,2008;Peters
indicatesubstantialconnectivity,oftenbidirectional,betweenthe
etal.,2008;Jinetal.,2010).ActivationofasingleSTafferentaxon
caudal NTS and most of the CNS (Herbert et al., 1990; Spyer,
reliablytriggersahighlysynchronousreleaseofglutamatevesicles
1990;Hermes et al.,2006;Geerling et al.,2010;Rinaman,2010;
fromallSTafferentswithnearlyzerofailures.Thissynchronous
Alheidetal.,2011;Alhadeff etal.,2012).Suchprojectionsoften
glutamateactivatesexcitatorypostsynapticcurrents(EPSCs)via
are part of bidirectional communication with other CNS inte-
postsynapticAMPAreceptors(Hermesetal.,2008).Antagonists
grative regions including the paraventricular and lateral nuclei
tonon-NMDAreceptorsfullyblockedSTevokedEPSCsinintra-
of thehypothalamus,rostralventrolateralmedulla,caudalraphe
cellularrecordingsfromsecondorderNTSneuronsandNMDA
nuclei,theA5 cell group,and the area postrema (Loewy,1990).
antagonistsalonewerewithouteffect(AndresenandYang,1990;
Thiscontrastswiththerelativelydiscretepatternsofaxonstoand
Doyle et al., 2002; Kline et al., 2007; Zhang and Mifflin, 2007).
fromPVNneuronsofthehypothalamusorthecaudalventrolat-
These ST-EPSCs arrive at very consistent latencies measured as
eralmedulla(EllacottandCone,2004;Benarroch,2005;Andresen
low jitter (SD of latency of <200µs) that indicate monosynap-
etal.,2007a;Rinaman,2007;Ulrich-LaiandHerman,2009).Dif-
ticconnections(DoyleandAndresen,2001;AndresenandPeters,
ferentprojectionneuronsfeaturefrankexcitabilitydifferencesin
2008).Incorporationofafferentdyelabelinginsuchexperiments
their ion channel expression which differently tune their action
show that dye placed on peripheral cranial afferent axon trunks
potentialoutputsalongthepathway(Baileyetal.,2007)andthese
was transported centrally and appeared as multiple fluorescent
ionchannelsoftenmaybethepostsynaptictargetsofneurotrans-
puncta contacting NTS neurons and identifying them anatomi-
mitter regulation through metabotropic receptors (see below).
callyassecondorderneurons(Mendelowitzetal.,1992;Balkowiec
AlthoughsomeoftheseNTSprojectionneuronsaresecondorder,
etal.,2000;DoyleandAndresen,2001;Klineetal.,2002;Chenand
some belong to a relatively rare class, higher order neurons in
Bonham, 2005; Zhang and Mifflin, 2007; Andresen and Peters,
theNTSthatlackdirectSTcontacts(Baileyetal.,2006a,2007).
2008).Suchdyeidentifiedneuronsshowedafferentboutonsonor
Whethersecondorderorhigherorder,ultimatelytheflowofcra-
near the cell body (a somatodendritic pattern) and when tested
nialvisceralafferentinformationresultsinautonomicregulatory
inbrainslicesevokedsimilarlylowjitterEPSCresponses.Remote
pathways of the sympathetic and parasympathetic nervous sys-
ST activation rarely activates NMDA receptors even using rapid
tems.AsshortasmanypathwaysthroughNTScanbe,itisclear
bursts of ST shocks in low magnesium conditions (Jin et al.,
that key integration occurs at the first synapse, i.e., the afferent
2003).IntransverseNTSslices,NMDAreceptormediatedsynap-
synapse.
ticresponseswerereportedin3–4-week-oldanimals(Aylwinetal.,
1997;Baptistaetal.,2005a)orasubsetofsecondorder,adultNTS
PRESYNAPTICCRANIALAFFERENTTERMINALS neuronswithmyelinatedafferents(Jinetal.,2003).Intransverse
Over75%ofallneuronsinthemedialNTSaresecondorderneu- slices,theSTandrecipientneuronsareincloseproximity(often
rons(McDougalletal.,2009;Andresenetal.,2012;McDougalland 200–300µm)butthecontributionsofthespreadoftheelectrical
Andresen,2012).SincetheA/Caxondistinctionextendstocentral stimulusbeyondtheSTorthedevelopmentalstateoftheanimals
synapseswithintheNTS,>80%ofallvagalafferentterminalsare are difficult to assess. Certainly, NMDA receptors were present
likelyC-type(Aicheretal.,1999;Andresenetal.,2012).TRPV1 onsomeneuronssinceexogenousNMDAselectiveagonistsacti-
reliably marks C-type ST afferent inputs but is never expressed vated small inward currents (Drewe et al., 1990) but, in many
postsynaptically,i.e.,withintheNTSneuron(Doyleetal.,2002; neurons,neitherNMDAnormassiveglutamatereleasewithcap-
Jinetal.,2004b;Andresenetal.,2007b,2012;AndresenandPeters, saicinevokedcurrentsundernon-NMDAblockade(Doyleetal.,
2008). Nodose neurons share similar biophysical distinctions in 2002). Thus, the participation of NMDA receptors in ST affer-
ion channels and excitability as occur in dorsal root ganglion enttransmissionhasbeencomplicatedandcontroversial(Baude
neurons.C-typeTRPV1+nodoseneuronsexpressTTX-resistant etal.,2009).TogetherthesefindingssuggestedthatNMDArecep-
sodium channels and have characteristically prolonged action torswerelocatedextrasynapticallyandoutofreachofsynaptically
potentialsintheircellbodiesalongwithsubstantialotherdiffer- released glutamate on second order NTS neurons (Doyle et al.,
encesinionchannelbiologycomparedtoA-typenodoseafferent 2002).Thissuggestionissupportedbyultrastructuralstudiesthat
neuronsincludingpotassiumchannels(Schildetal.,1994;Schild showedNMDAreceptorsmostlylocalizedtoextrasynapticmem-
andKunze,1997;LiandSchild,2007;Lietal.,2007,2011;Zhou branesratherthanwithinasymmetricalsynapsesadjacenttovagal
et al.,2010).As a result,C-type neurons display much stronger afferent terminals (Aicher et al.,1999). Interestingly,these same
frequency dependent action potential broadening which limits structuralstudiesindicatedthecommonpresenceofpresynaptic
repetitiveexcitation. NMDAreceptorsonvagalafferentterminals(Aicheretal.,1999),
www.frontiersin.org January2013|Volume6|Article191|5
Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
although no functional studies have indicated their role. Thus, TRPV1−secondorderNTSneuronsregardingadifferentmode
fast synaptic transmission generates large reliable EPSCs for all of glutamate release – basal or spontaneous glutamate events.
STafferentfiberswithsimilarfrequencydependentdepressionfor Spontaneous release has long been thought to result from sto-
bothTRPV1+andTRPV1−afferents.Thisfrequencydependent chastic,rarespontaneousfusionsfromthereadilyreleasablepool
depressionresultstosomedegreefromvesicledepletionaswellas of vesicles – that is vesicles staged and primed for release (Katz,
otherautoreceptorfeedbackmechanisms. 1971;ChungandKavalali,2006;Kavalalietal.,2011;Ramirezand
Onedifferenceinfastglutamatergictransmissionthatroutinely Kavalali, 2011). The similarities in fast glutamatergic excitatory
distinguishedC-fibersSTtransmissionwastheirstrongtendency transmissionbetweenA-andC-typeSTafferentinputsmayhave
to fail in a use-dependent manner. TRPV1−, A-type ST affer- delayedrecognitionofwhatinhindsightshouldhavebeenobvi-
entsrarelyfailed.Onasingleshockof activation,TRPV1+and ous(Petersetal.,2010,2011;Shoudaietal.,2010).NTSneurons
TRPV1−afferentsfailedonaveragelessthan1%oftrials.Athigh withC-typeafferentsexperienceda5–10-foldhigherspontaneous
frequenciesofactivation,failurerates(missingEPSCsperstimulus rate of EPSC activity. These high rates of EPSCs in TRPV1+
shock)approachedratesof30%forC-typeafferentswhileremain- NTS neurons were unrelated to afferent activity since they per-
ing below 5% forA-type afferents (Andresen and Peters,2008). sistedwhenactionpotentialswereblockedbyTTX.Infact,high
Thus,thebasicmechanismsofsynchronousglutamatetransmis- rates of action potential driven activity caused depressed syn-
sionaresimilarbutitmaybethationchanneldifferencesimpact chronousreleasebutspontaneousreleasewaselevatedsuggesting
the invasion of terminals or their central conduction that fails thattwopoolsofdifferentvesicleswereresponsible(Petersetal.,
moreofteninC-typeafferentsthanA-typeafferents.Thedynam- 2010, 2011; Shoudai et al., 2010). Antagonism of TRPV1 (e.g.,
ics of synaptic failures may indicate successful invasion of the SB-366791)decreasedspontaneousreleaseatNTSneuronswith
synapticterminalandmayoccurdistallyandoutsideoftheelec- TRPV1+STafferentswithoutalteringtheamplitudeofsynchro-
trotonicinfluenceoftheterminal(Baileyetal.,2006b;McDougall nousEPSCs.Inaddition,thespontaneousorminiature(inTTX)
etal.,2009).Sincethetwoafferentfibertypesandtheirexcitability release rate closely followed changes in temperature between 30
areintrinsicallydistinctinmanyways,theuse-dependentfailures and37˚Csuggestingthattemperatureeffectivelygatedpresynap-
mostlikelyreflectsthebehaviorofthoseionchannelsinregener- ticTRPV1receptors.Thus,TRPV1inSTterminalsactivelydrove
ativespikegeneration(Schildetal.,1994;SchildandKunze,1997; thereleaseofglutamatevesiclesatphysiologicaltemperaturesand
Li and Schild, 2007; Li et al., 2007). These differences between violates the canonical view that TRPV1 receptors have thermal
conduction and vesicle release are important to understanding gatingthresholdsof>43˚C(JuliusandBasbaum,2001).Prelimi-
receptormediatedmechanismsandsitesofmodulation. naryworkindicatesthatbothasynchronousreleaseandthermally
Detailed analyses of low jitter ST-EPSCs indicated that they evoked release are attenuated in TRPV1 knockout mice (Peters,
arosefromanaverageof18–25activecontactsthatformtheEPSC 2011). Activation of TRPV1 may depolarize synaptic terminals
(Baileyetal.,2006b;AndresenandPeters,2008;Petersetal.,2008). through its cation selectivity and inward current,a process that
Suchafunctioningarrayof multiplecontactsisquiteconsistent can activate voltage-activated calcium channels to release gluta-
with labeling studies of ST afferents which showed varicosities mate.ThecationselectivityofTRPV1constitutesadirectpathway
resembling multiple release sites distributed along single axons fortheinfluxofcalciumionsintotheseterminals(Caterinaetal.,
(Anders et al.,1993;Kubin et al.,2006). The redundant contact 1997).Blockadeof voltage-activatedcalciumchannelswithcad-
patternrequiresreleasesitesformedbyenpassantcontactsfrom mium did not alter spontaneous rates of EPSCs but blocked ST
eachafferentaxonandthemultiplereleasesitesgeneratethevery evokedsynchronousEPSCssuggestingthatTRPV1providedthe
largeandreliablesafetyfactoroftransmissionbetweensingleaffer- calcium for spontaneous vesicle release (Fawley et al.,2011). In
entsandthesecondorderneuron.Theprobabilityofsynchronous the presence of cadmium, thermally evoked increases in mEP-
glutamate vesicle release from a readily releasable pool averaged SCs persisted (Fawley et al., 2011). Overall, ST TRPV1 is quite
a surprisingly high 90% in an external calcium concentration activewithinarangeofphysiologicallyrelevanttemperaturesand
of 2mM.However,theamplitudesof theseST-EPSCsdecreased TRPV1-operated glutamate release represents a novel and tonic
substantially when activation frequencies were above 50Hz – a signaling mechanism that releases neurotransmitter even in the
physiologically modest frequency for naturally activated myeli- absenceofafferentactionpotentials.Itisparticularlyinteresting
natedafferentsbutanearmaximalfrequencyfortypicalC-fiber thattwootherligand-gatedionchannelsareexpressedonSTter-
afferents. Remarkably however,the key features of fast synchro- minals–theserotoningatedchannel,5-HT3,andthepurinergic
nous glutamate transmission were indistinguishable betweenA- P2X3 channel – and in many respects these channels resemble
andC-typecranialafferents.Thissynchronousglutamatemecha- TRPV1 signaling in being permeable to calcium and capable of
nismreliablyevokesactionpotentialsinthepostsynapticneuron influencingvesicularneurotransmitterrelease(Glaumetal.,1992;
andpresumablyconductsthisinformationbeyondtheNTSupto Doucetetal.,2000;Jinetal.,2004b;Mazdaetal.,2004;Wanand
frequenciesofabout20HzbeforetheEPSCdepressestobecome Browning,2008;Cuietal.,2012b).However,neither5-HT3nor
lessreliableathigherfrequencies(AndresenandYang,1995;Schild P2X3appearstoinfluencebasalreleasetonically,apointwhichfur-
etal.,1995;Liuetal.,1998). therdistinguishesTRPV1asatonicsignalthatdoesnotrequire
neuralactivation.
MECHANISMOFDISTINCTION–TRPV1-OPERATED A-type cranial visceral afferents generate synchronous EPSCs
GLUTAMATERELEASE buthaveverylowbasalspontaneousglutamaterelease.Incontrast,
Given the fundamental similarities in synchronous glutamate C-typeafferentshavesimilarsynchronousEPSCs,butreleasesub-
release,asurprisingdifferencehasemergedbetweenTRPV1+and stantialnumbersof glutamatevesiclesspontaneously.Activation
FrontiersinNeuroscience|NeuroendocrineScience January2013|Volume6|Article191|6
Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
of action potential driven synchronous EPSCs enhanced the theirmyelination.LittleisknownabouttheaccessoftheseGPCR
TRPV1-operatedvesiclereleaseforaperiodofsecondsandpro- signal transduction to the TRPV1-operated mode of glutamate
ducedasynchronousreleasesufficienttotriggeradditionalaction release.
potentials in the postsynaptic neuron (Peters et al., 2010, 2011;
McDougallandAndresen,2013)inbasalconditionsthatareincre- NOVELNTS-TRPV1SIGNALING
mented even higher in an asynchronous mode of release. The FatandmembranelipidmetabolitesarenewlyappreciatedasCNS
physiological meaning of the TRPV1-operated pool of vesicles signaling molecules (Pingle et al., 2007; Scherer and Buettner,
is only beginning to be appreciated. This TRPV1-operated pool 2009;DiPatrizioandPiomelli,2012).Lipoproteinsandmetabo-
hasbeenimplicatedaspotentiallyplayingaroleinthelaryngeal litesincludinganandamide(AEA)likelyactasendocannabinoid
chemoreflexandtheexaggeratedapneainanimalmodelsofSud- and/orendovanilloidsignalingmoleculesthatalterreflexfunction
denInfantDeathSyndrome(Curranetal.,2005;Xiaetal.,2007, when introduced into the NTS (Geraghty and Mazzone, 2002;
2008,2010,2011).Morecomprehensiveinvestigationsareneeded Brozoski et al., 2005, 2009; Seagard et al., 2005). Co-expression
tofullyevaluatethisnewformof afferentsynaptictransmission of the cannabinoid receptor (CB1) and TRPV1 is common in
anditsimplicationsinmulti-systemhomeostaticregulation. dorsal root ganglion neurons (Amaya et al.,2006; Binzen et al.,
2006). CB1 and TRPV1 interact with lipid derived mediators
METABOTROPICSIGNALING such as arachidonate, 2-arachidonoylglycerol,AEA, eicosanoids,
Ionotropic receptors for glutamate and GABA are the mainstay epoxyeicosanoids, and prostaglandins. AEA was detected in the
for excitatory and inhibitory transmission (respectively),within dorsalvagalcomplexsampleswhichincludedtheNTS(Seagard
the NTS. Integration, however, even at second order neurons et al.,2004;Chen et al.,2009) and theAEA content in the NTS
is highly differentiated through both homo- and heterosynaptic regionincreasedwhenbloodpressurewasraised(Seagardetal.,
interactionsbyglutamateandGABA.Withmultiple“accessory” 2004).However,thebiochemicalpathwaysforgenesisofpotential
transmitterspresentintheNTS(especiallypeptides,seeabove),the lipidmediatorsarecomplexandinterconnectedsothattheulti-
interactionpotentialblossomsandassessmentsrequirequiteelab- mate active compounds and cellular signaling are often difficult
oratetestingtoestablishcauseandeffect.Muchofthisinteraction to establish (Buczynski and Parsons, 2010; Katona and Freund,
utilizes metabotropic receptors which employ second messen- 2012).DepolarizationofNTSneuronsreleasedanendocannabi-
ger signaling (Conn, 2003). Metabotropic glutamate receptors, noid that controlled GABA release via CB1 (Chen et al.,2010).
mGluRs,powerfullymodulatebothSTafferentglutamaterelease Although CB1 generally inhibits neurons and neurotransmitter
aswellasGABAreleasebypresynapticmechanisms(Glaumand release (Derbenev et al., 2004), AEA not only inhibited gluta-
Miller,1993;Foleyetal.,1999;Hayetal.,1999;HoangandHay, mate release via CB1 activation but also enhanced release via
2001; Chen et al., 2002; Jin et al., 2004a; Browning et al., 2006; TRPV1activation–dualopposingactionsonacommonbiological
Browning and Travagli, 2007; Austgen et al., 2009; Fernandes process(Tognettoetal.,2001).Experimentaluseofplantderived
et al., 2011). These presynaptic effects are heterogeneous and, agonists and endogenous ligands may be confounded by this
depending on the subunit composition,can be negative or pos- TRPV1-CB1interaction.N-Arachidonoyl-dopamine(NADA)is
itiveregulatorsofneurotransmitterreleaseevenacrossotherwise anendogenous“capsaicin-like”substancethatcanactatTRPV1
similarsecondorderNTSneurons.Inaddition,mGluRscanmod- (Huangetal.,2002).Suchparadoxicalactionsofsubstanceswhich
ifypostsynapticcurrenttoalterNTSneuronexcitability(Sekizawa crossovertoactivatebothCB1andTRPV1arenotwellunderstood
andBonham,2006).Littlesystemspecificinformationexistsfor especially in systems in which these receptors are co-localized
theseinteractionsintheNTSparticularlyregardingwhichvisceral including primary afferents (Ahluwalia et al., 2000; Price et al.,
afferents are involved or the specific destinations of projections 2004). Lipids together with various inflammatory cytokines are
outof theNTS.TheTRPV1-operatedpoolpresentsanewchal- linkedtotheNTSandcorrelatedtothedevelopmentof chronic
lengesincepharmacologicalassaysof spontaneousorminiature hypertensionandobesityinhumans(Chaeetal.,2001;Katagiri
glutamate events may not be representative of synchronous or etal.,2007)andinanimalmodels(Wakietal.,2008;Wangand
afferent driven mechanisms (Fawley et al.,2011). Because these Wang,2009;Takagishietal.,2010).Forexample,systemicinjection
receptors are present in multiple pathways, functionally impor- oflipopolysaccharideorinterleukin-1βtriggeredsustainedgluta-
tant interactions may be triggered during drug interventions in matereleasefromtheNTSthatwaspreventedbyTTX(Mascarucci
theNTS.Therefore,differentialexpressionofspecificGPCRsmay etal.,1998).ProstaglandinE2depressesonlyTRPV1+STevoked
helptospecificallytuneindividualpathways.PresynapticmGluRs EPSCs in NTS neurons (Laaris and Weinreich,2007). Cannabi-
arecommonGPCRsintheNTS(Hayetal.,1999;Jinetal.,2004a; noids are implicated in central plasticity and in cyclooxygenase
Fernandesetal.,2011)andpresynapticexpressionofGPCRsfor metabolismtoprostaglandins(YangandChen,2008;Heifetsand
peptidescommontoperipheralorforebrain(e.g.,hypothalamus) Castillo,2009).Thus,thepotentialforsignalingcrossoverbetween
neuron sources distinguishes ST transmission at many neurons. CB1andTRPV1isconsiderable,complex,andpoorlyunderstood.
These peptide GPCRs are primarily presynaptic on ST afferents TRPV1-operatedglutamatemechanismoffersanewfocalpoint
butgenerallyhavemuchmorelimitedrepresentations.GPCRsfor for the integration of multiple signals with substantial clinical
angiotensin(AT1),vasopressin(V1a),OT,opioid(MOR),ghrelin importance. Intriguing clinical and basic observations point to
(GHSR1),andCCKdifferentiallycontrolglutamatereleaseonlim- multipleriskfactorsformulti-organsystempathologythatrelate
itedsubsetsofneurons.Noclearassociationshavebeenestablished directly or indirectly to cranial afferents, TRPV1 and NTS sig-
between particular GPCRs and different afferent modalities or nal processing. One extrapolation of these complex correlations
www.frontiersin.org January2013|Volume6|Article191|7
Andresenetal. Co-transmittermodulationofafferentglutamateinNTS
concerns inflammation, a well recognized co-factor in multi- is reported in neurogenic hypertensive rats (Waki et al., 2008).
ple diseaseprocesses that impacthomeostatic systems. In spinal Interestingly,inflammatorycytokineresponsesininduceddietary
dorsalhorn,TRPV1ispartofachronicpathologicaltransforma- saltlinkedformsofhypertensionaremodifiedinTRPV1knock-
tion of afferent signaling (allodynia/hyperalgesia; Holzer, 2004) out mice (TRPV1−/−;Wang andWang,2009). TRPV1−/− mice
butwhetheranalogouschangesoccurintheNTSareunknown. are reported to be resistant to obesity from high fat diets that
Markersofinflammation,e.g.,interleukin-6,arepositivelycorre- induce low level inflammation (Motter and Ahern,2008). Such
latedwithincreasesinbloodpressure(Chaeetal.,2001),stress, associationsandrolesforperipheralvs.centralTRPV1receptors
andhypothalamic-pituitary-adrenalaxisactivation(Serratsetal., arepoorlyunderstood.Thus,thedeficitininformationregarding
2010)withelevatedmorbidity(Katagirietal.,2007)andTRPV1 C-fibersandTRPV1intheNTShasbroadpotentialimplications
targeteddrugshavebeentoutedasanti-inflammatoryagents(Tsuji thatarecriticaltounderstandingpathophysiology(Szallasietal.,
etal.,2010).InflammationwithincardiovascularareasoftheNTS 2007;WongandGavva,2009).
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