1

existence of two in the nucleus traclUS solitarius in the dorsornedial rnedul­

cord are described.

of

One of these

cn2lpu~r describes '"'l"<'" .............. " of blood

to innervate the sym­column in the thoracic

The pressor function of the yentral surface of the medulla was first demon-strated and Guertzenstein , who ductlons in arterial pressure by the bilateral application of IJ ..... 'HUVC ..

sodium. the of localized the of the surface of the ventrolateral

the ventral surface of the medulla. Further the """",·ccr, ..

neurons of the B3 group of

in the rostral ventral medulla. Renewed in-was kindled the evidence that [he

3

4 J. et 01

;:,!OSTRAL MEDULLA

~.~EDULLA

SPINAL COAD

rp.r.rp',l"nt""',"n of some of (he .... ·)I'",,·.\"CO

the nucleus tractus solilDrius and rostral ventrol()[er,:d medull~L

neu fans wi rh loeat or distant cell bodies also 10 Ihe CVUv! and RVLM.

neurons

the caudal

Al neurons be ng et al \ 1981! West et L, J Whlle it is now clear thiH (he pressor and sor functions of these areas are not of the individual activities of the Cl BJ serotonin. or Al noradrennline cell

well esrablished fhat the ventrolateral medulla is a of blood pressure and of cir­

culation. The neurons arise in (he rosrral vemro-

lateral medulla from the obex to the nucleus of the facia! nerve, "J\.J..:II-J'l 11.[;.1 I neurons are found in the nrea of lhe Cl

neurons first described nC"'T'''f'f'''',~(" such as

I, Afferent Tnpu(s (0 Vc-ntrol.<lter:ll Jvledulla 5

no acids. which are colocalized in a variety of combinations. Mc also found In rhe area. Bulbospinal n~uron$ are also 'found more medially in (he "reas ot the serownin-containing neurons that make up the lateral elements of

the B3 cell group (Howe et aL. 1983; Pilowsky er nC, 1986b: NIi nson et aJ., 1987). Some of lhese neurOns contain $ubs!ance P and othe r putative neU(ot(ansmit\~rs (Joha.nsson et al.~ \981; Sa.sek er al. \ 1990) Cox nnd Bredy (1989 a ,b) have suggested [har these (wO regions should be termed the rostral ventrolateral medull;) corresponding to (he Cl region and the rostral venlromediaJ medulltl corresponding to the BJ region. Bulbosptnal

neurons from DOlh or these rostr()j pressor regions send axons to [he inter­mediolateral CEll column of the thor~('ic spinal cord (Fig. l.L Blessing et ~d .. 1987: Johansson eT at.. 198L Minson et a\.. \987; Pilowsky et aI., 19B6a). Furthermore. synapses on identified ~ympo.thetic preganglionic

neurons have been demonstrated from nerve termil1aJs conlain.ing phenylerhanolZ)mioe-N-methyltrf'lnsferase (PNMT), NPY. serotonin, sub­

~tance P, and glutamate (B<1con nnd Smith, 1928; Kohno el al.. 1988; L1ewellyn-Srnith et al.. 1990; Morrison et £)1,. 1989: Reis er al .. \988).

Tile caud.:.d ventrolater~1 medulla is now well csrablished :lS ;] depressor region :lnd it seems likely thtH it oper'UeS.i\l least In part through rhe Ionic JCTivity of Cl shon ascending Inhibiwry projection (Fig. l.}) that acts to inhibit lhe pressor etfecls ef the s~mpalhocxcit~lOry bulbo~pin<ll pressor

neurons descending· from the rosuill ventrolateral medulla (Fig, I.t; Pilowsky et al.. 1986b; Blessing and U. 1989: Dembowsky et aL. 1989). The Identity of the neurC>(fan~miller in this shorl ascending projection has not been cle,)Tly established but Lhere is evidence Sllggesiing ir might be

ganlmn-aminobutyric :tcid (GABA) (BleSSing ('lnd Lt_ 1989),

Afferen[ Inputs lO the Ventrolateral wledulla

Although there is now Cl grear deal of knowledge about the pressor and

depressor regions in rhe roslr~1 and caudal ventrolateral medulkl <lnd rheir descenolog bulbospinal projecrions, there has been much less work on the afferent Inputs that regulote the activiry of bulbospinal neurons, I[ has long been established that arterial b,)foreceptor neurons terminate in the nuc­leus tractus soJi[anus in the dorsamedin/ medulla. However, where~s it is clear (hat there is a substantial projection from the nucleus (raCHiS solitar­ius to the venlrOlllteral medUlla (Blessing and Li, 1989; Dnmpney et aL, 1987: Loewy and BUrlOll, 1978; Ross e( al., 1985; Spyer, 1981), Ihere is liltle knowledge of what lleurotransmitters these afferent fibers contain.

Recent reports from our la.bor~[ory have identified [WO such pathways,

one containing exci[cllory amino acids (Somogyi e[ aI., 1989) and Ihe orher contZlin iog enkephalin (Morilak et al. I 1989). These IwO projections afe

described b~roVJ, together with physiological and pharmaco'ogica\ sfudies 011 their possible participation in the regulation of blood pressure.

6 LP. Ch ~ lmu~ C l :J I.

ExcilaLOry A mino Acid Projection from Nucleus Tractlls So/ifarius (0 Venrrolmeral Medtdla

Th is swdy was promp ted pM! I)' by (he obscr vations 11'131 bnroreceptor re Aexcs ca n be blocked b~ e~C i(alOry amino acid al1l3gomSIs injected inlo the ventro late ral meduHa (Go rdo n 1987; Guyencl c l al. , J987; Kubo and Kihara, 1985).

Relrograde a ~on al l ranspo Tl of tri lla lcd -D-as pan:llc was used in our ex­periment s as fu lly des~ r ibed eI~e ll'he re (Soma!y; e l a l. . 191::19). This com­po und has been used ex(ensive ly fo r the specific ide ntification of ( c nl{al pa thways using cxci1.ato ry am ino acids as lransmillen (Cuenod a nd Slrell. 198<1). In o rde r IQ I race: cxci t:uo ry amino acid pro jection s 10 the ve ntro­la te ral me:dull a , Irili,lI cd- D-aSpMtal c was in jcCled inlo Ihe pressor region o f Ihe r05lral v~ OIrolaler :l1 medulla o r iOlo Ihe depresso r region of [he caudal ve nrco l.u e ral medulla of r;l lS. Whe n injeel ed inlD Ihe rost ra l pressor region , Iril ia led-D-asparl:ll e evo ked a presso r response whe re as when it was in i~c led inlo Ihe caudal depresso r a rea. il eaused a r,.. 1I in blood pressu re.

An .... r in jeclions of labekd asparr r:t le inlo eithe r Ihe rOSlr ... 1 o r caudal ven­Iro lat e r;l l me dulla , mo re th an 90% of [he neu ro ns Ihal sd eclive ly accumu­lalcd Ihe marke r in Ihc medulb we re In the nuck us IraclUS soli ta rius. mainly ipsilale cally. wit h few ce ll s labek d in [he ven tro la te ral medulla. None o f Ihe Ileu rons l:lbe/ed in tIle nuc!t::us 1r,1CIUS solilarillS we re Im· rnu no reaclive fo r GA BA o r (or PN MT. Injec tio ns o f rhe nOllspecifk re· trograde {facers. whe;uge rm·go ld or \vhc i'u gc rm. horse r,ldish peroxidase (HRf') mlo Ihe ve nj rolale ral medulla resu fl ed ill compa rllble densi ty of labe1i ng of Ihc nudeus I faC tuS solirarius, sHggesling thal mOSI neu ron s pro· jec ti ng fr om {he nuc leus (r:lCt US soli t.)riu s co lhe vcnu obte ral med u li :) also accumu la te IrIC i.l led- D-aSpMIi"l te . However. in conuaSl lO Ihc specific ami · no acid mar ker. Ihe no n\pc:citlc wh.: arge rm conjug:Hcd lu a rs 1,1beleJ numerous ne urons arou nd the injeclion site as we ll as o lhe fS in both th~ rosIT;! 1 and ca udal ve nlTo la [era l medull l . These tJa tJ I hu~ conormed p re ­vio us repo rrs o f co nnections bc lIVeen IIIe rostral and .:.l lldal ve nu ohl e ral medu!l <l (B less ing e t aL, 1987; Reis e l al. . IIJRS : Ross cl al. . 1935). Fu r­thermo re. {he spMsil!, o r b be1ins ..vilh the spec.: illc ;"I mino acid marke r suggested {h ill mos e 01" these ne uro n:" do not use exc je a10ry amino ac ids lIS [f3nsm iu ers (Somogyi el al. . 19S9) . Th~ funCllonal significa nce of Ih is CXci t:r IOry amino add pa lhwlly was

lested using injeclio ns o ll he select ive N·melh:-- I- D-asp;rrlate (NMD A ) re ­cep rOr a n lilgonis l 2-arnillo-5-phosphonov:ller:ue (2A PV) (O;:wies el 31. , 1981) inco ph ysiologically iden lifled de presso r siles in Ihe ca udal ve n lro· late rlJ l medull a . These Injeclio nscaused a rise in ane r1<1 1 p ressure In 'he rat a nd co mplet e ly a bolished Ihe depressor effects of L-glulama lc injecled int o the i p5 i1 au:I"~ 1 nucleus Ir;rCIUS solilJ rms. In Olhe r e~perime n l s 10 anes lhc· tized rabbits, bilnle ra! injectio ll of 2.o.. PV inlO Ihe c41 uda l ve ntrola[ c ral

•

I. Atluenl InpllIS 10 VClllrolarer:t1 Medu ll:t 7

medulla produced a me 10 blood prcssure and block~d Ihe depressor r~· :ipOflse evoked b~ elecrrrcal Stlmulilllon of the <lOfHe depressor n~rve (Somogy i et aI., 1989). These e.'(pcnmenrs :lro=. lilerefore in a~eement wll h previous I(POrlS Ih.u Ihe: e:o;cnarory .. mino acid proJeclions from Ih~ nnc· kos Ir .. crus soliulOus parhC'pille in botn tonic and re !'le:< regula lion of rhe circul;u ion (Gordo n. J9~7 ; Guyenel e t aI., 1987: Kubo 2nd Kihara . J983 : Urba nski and Sapru, 1988) .

Since the re IS evidence rh .. , both the roslral pressor and the eaudal de­pressor ne nrons are lonicall y active, it mighr seem somcwhal paradoxlcJI Ihal the e.'(c it a to ry tlm jno aCid p:)fnway rrom the nuclcus H;'IClUS solitarius shou ld prOjec t 10 bOlh regions (Somogyi ct al.. 1989). One e .'(pl~nalion

migtll be Ih ... the dislribulio n o f Iht: depressor neurons o~'erlap wllh Ihe presso r neu rOns more roslra ll ~ . Soch depressor neu rons. possibly contain­IFlg GABA ns an inh ibitory neufotram,m iller acti ng direclly on Ihe pres..<;or neurons. mIght be la rge ls fo r the excil:lI o ry amino aCId project iollS from Ihe nucleus IraC/us w liEMius. 11 is also possible th'lI the excilatOr~ amino ACId projecl1on 10 Ihe rostra l venlrOlatera l medulla is a pressor p:lIhwtly whose activity could acco unt fOf thl! reversal of the dfects of nucle us Irac· IuS solifanu5 Slimulation from a d c= prcssor 10 a pre:isor response aller injec­liOnS of nlUscimol (Urbans!.:! and S"PfIJ . 1988 ) or 2A PV (Somog:-,i et:11.. 1989) IrHO Ihe caudal ventrolateral nledull<l. or of blcucu lhne inw Ihe ros· Iral ven rrolatualmedulla (U rbanski J.nd Sapru. 19X5)

It shoukl be noted Ihat BleSSIng (t9tN) has reporll!J Ihn t where .. s injec· lion 01 2APV 11'110 the c: .. udal ventrol;'lteral medull:l bloc~s {he vasodepres­sor response and the ren .. 1 sympa thoinhibi tory response evo\':eu by ele~· Irical stimulation of the aortic ciepressor oerve. Lt does nOI affect the baroreceptor vasomotor response!. 10 raising or lowering anerial pressure (Bles~ing. 1989) Although rhese discrepancies are difficult 10 reconcile. one possibili ty IS thlt the residual b;uoreceplOT rdlen:s re lie" :lCIIVatlon of afferents from the carOlid zones Or (rom IOW pre ssurc rece ptors A r}()lllI.: r possibilit y is Ihl\ renal sympalhe llc ne rve activity is not represenlative of penphe ral s~mpalhetic acrivilY as a whole. as has been illustrated by the cxpercmefllS of Cox and Brody {19S93.b). who have shown selecllve aCllva­lion of renal and mesenr~ric s}'mpalhetic nerves by SlImulallo n of the ros­Ifa l vemTolaLeral or the rosrral venrromedial medulla . re speclivcly

Enkephalin Projection/rom Nucleus Tracws Soiirarius lO

Ventrolateral Medulla

Previous st udies have demonstra ted the presence of enkephalin-conlJrning .:ell bodies in 'he nllcleus Iractus SOli lMius (Armslfong el al., 1981 ; Finley el al.. 1981; KhaChaturian el a I. , 1983; Yamazoe el ill .. 1984) and of ~nk.ephalin.conlaining nerve te rminals in tht: ve ntfo!;He ral medlllln (Elde e t al.. 1976; Finley et al.. 198 1; Knac hat ufla n el a I. , It)S3; Simtlnlov et aI., 1977), but none hlls esta\)lished Ihe prese nce o f .. n opiale pa lhw<1Y connee, -

8 J.P. Chalmers et al.

these Accordinglv, we to determine the origin of in-tramedullary enkephalin-colHaining pa[hways terminating in the pressor area in the rosrral ventrolateral medulla of the rabbit (IVlorilak et aL, 1989).

A technique of wheatgerm conjugated colloidal particles with immunohistochemical demonstrDtion of enkepba\jn-like immunore;)ctlvity was used for this purpose. The rostral ventrolateral medullary pressor W<:IS first localized by of

and slow were then made at the same coordinates. A res! ricted injection site resulted, corresponding to the Cl pressor area, a$ verified by the presence of cyrosine hydroxylase and neuropeptide Y -containing neurons (tvlorilak et 31., 1989).

After silver incensiticacion, gradely appeared as black granules in the cytoplasm of neurons. labeled cells contained bmh the black silver indicative of retro­grade transport and homogeneous brown immunoperoxidase reaction product, indicative of Wichin the nucleus tractus soli tari us \ labeled cells were observed in the commissural nucleus and in the intermediate subnucleus at the!evel of the obex and rostral to the obex (ivlorilak et aI., 1989). Ce\Jsin the nucleus tractus so!itarius other trnnsmilters such as substnnce

Y, nnd catecbolamines did not show the same de­gree or patcern of double . that the transport was nor due to nonspecific silver reduction or spread. This from the nucleus tr;)ctus solit<)fius (0 the rostra] ventrolateral medulla could repre­sent a major cenrra! substTate underlying effects on the cmdiovascu­lar system.

Functional of Opioid Inputs to Ventrolateral Medulla

'.More recently we have scudied the cardiovascular effects of microinjection of the antagonist naloxone as well (lS microinjeccion of selective opioid antagonists ineo the rostral and caudal ventrolateral medulla of the rabbit er [11., 1990a Droler et a!.,

observa tions). Bilateral of naloxone the pressor afea of

rostra] ventrolateral medulla induced a gradual and prolonged increase in mean arterial pressure (Morilak et a1., 1990a), When naloxone was administered into the rostr<ll ventrolateral medullii <iftcr a moderately severe (20 ml of blood per kg of body weight), it

recovery of blood pressure relative to saline contro!s, again in­ducing a but long-lasting pressor response. The effects naloxone 00 the baroreflex of inract 3nimals was transient and minimal. These ex­

that endogenous opioids exert (l tonic inhibitory in-

l. Afferent to Ventrol;tteral Medulla 9

.... VlllUL.J0'-- after

we have examined that could be activated

blockade of mu funalrrexamine or of

inlo the rostral ventroiarerat medul1a had no effects on either blood pressure or heart rare er aJ., . However. spe­ciRe blockade of delta receprors in [he ros(ral ventrolaTeral medulla follow-

bilnteral Of the reI l74 864 caused and Jas[ed

or of the inactive

IS therefore suggest that the to the rostral venrroia[eral medulla inhibirs

activarjon of delta receplOrs

The caudal ventrolllteral medull;.l nlso receives cootai nerve terminals (Elde, el al .. 1 chaturian er al.. 1983; Sirna ec al .. )

The caudal ventrolmeral medulla response that

et aI., that there etre active

to the cnudal ventroll1tefLil medulla [hal serve [0 inhibit [he pn,-pe-rAt"' neurons situared in this Ilfel:\ rhat may use either or 'n",,-,,,,,,,,,, n as neu ror ransmitters. These swdies suggest the pfcsence of distinct to both [he

rostr(ll and [he cauda! ventro!ateral medul which coouiburc to the con-rrol of blood pressure inhibirion of the rosrrrd pressor neurons nnd of the caudal neurons. The site of these not been identified, bur le is sible that in the nucleus tractus 501-

has now been described et aJ ,

a

The internction belween excitil(Ory amino acid .and to the caudnl ventrolateral has been studied in some

and of 2APV into the caud£lJ ventrolateral medulla

IQ J. P. Ch('))mers er al.

enhanced (he depressor effect of naloxone injecred inro (he same area 15 min later. On (he other hand, precreatment with naloxone injected iow rhe caudal ventrolateral medulla signitlcantly attenuated the pressor response to 2APV, given 15 min later inco the same si(c (Badoer and Chalmers. unpublished observations). The specif)city of ·these resulrs is currently being rested using pretreatment with rnuscimol and bicucu!line Injected into [he caudal ventrolateral medulla before admini.s(racion of naloxone and 2APV 1 respectively (Badoer ond Chal mers. unpublished observa­[ions) .

Conclusions

We have demons(rated that excitatory amino ilcid-conraining neurons project from the nucleus tracrus solitarius [0 the ventrolDleral medull::l and have confirmed that [his parhway is involved in the LOnic nnd retlex con~ HO! of blood pressure . \Ve have also shown an enkephalin-containing pnrh­way connecting these two areas but do not yet know whether it has a role in cardiovascul~r reguJ£}fion. Nevenhe!es$, opiold path\-'J"~'s of unkllov.;n origin (hal terminClte in the ven!rofateraJ medulla have been implicnred in blood pres~ure control by pnZlrm;)Co\ogical studies in our own Jnd orher laboratories.

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Blessin.g \VW (1989): Baroreceptor-vilsomowr reflex after N-methyl-D-;tsparate receptor block<lde in r:lbbit caudal ventrolateral medulla. J Physiol 416:67-78 .

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12 J. P. Chalmers et al.

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