-
`
`Enclosure:
`
`re: EP i 957 i06
`of July 11, 2014
`
`Reitstotter Klnzebach
`
`The Headaches
`Third Edition
`
`EDITED BY
`Jes Olesen, M.D.
`Proressor and Choirman
`Oepartmcnl of Neurolog,v
`Glos1rup Hospital
`Univershy of Copenhagen
`Gloslrup. Copenhagen. Denmork
`Peter J. Goadsby, M.D., Ph.D., D.Sc.
`Professo,· of Clinical Neurology
`lns1i1u1c of Neurology
`The Na1ionnl Hospit31 for Ncumlogy and Neurosurgery
`London. United Kingdom
`Nabih M. Ramadan, M.D.
`Professor and Chnir
`Department of New-ology
`Chicago Medical School
`Vice President
`Jncerprofessional Advancement
`and Communily Reln1ions
`Rosalind Fr ... nklin Unive~lty of Medicine and Science
`Chicago. Illinois
`Peer Tfelt-Hansen, M.D.
`Professor
`Depnnmenl of Neurology
`Glo:,.trup Hospiull
`Unl,·crsity of Copenh:igen
`Glomup. Copenhagen. OcnmJ.rk
`K. Michael A. Welch, M.D., Ch.B., F.R.C.P.
`Professrir
`Ocp:ir<mem of Neurology
`Chirngo Mcditol School
`P.-c. idcnt :md CEO
`Ros:.ilind fr:1nklin Universltv of Mcdidnc onJ Science
`Chh.--:1go.-lllinois
`
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`The headaches/edited by Jes Olesen ... [et al.).- 3rd ed.
`p.;cm.
`Includes bibliographical references and inde."l.
`ISBN 0- 7817-5400-3
`I. Olesen. Jes.
`I. Headache.
`[DNLM: I. Headache. Wl. 342 H4329 2006)
`RB l28.H44S 2006
`616.8'491-<lc22
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`·,.
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`.....
`
`CGRP Involvement in Migraines
`
`Lars Edvinsson and Richard Hargreaves
`
`Tlw lunclinnal sludies crucial to any hypolhesis regard(cid:173)
`i11;: prinwry (migraine and clllster) headaches resL~ nn the
`, b,,ic observations of Ra,v and Wolff ( I .2). who desc1ibed
`p:11111111 sensations that resulted from mechanical or elec-
`1.-in1I ~timllla tion of large cerebral aneiies, venous sinuses,
`aml dural arteries. The pain-sensitivl? supraLentorial strnc(cid:173)
`uir..:. I hut not subtentorial clements) are innen·ated by sen(cid:173)
`'"' · 11igeminal nen•e fibe1 arising from pseudeounipolar
`,,·1bo1Y neurons with their cell bodies in the trigeminal
`~;111~lion. Tl1e ccntrnl projections from these neurons con-
`11~.-1 into the crn trnl nervous sys1em (CNS) al second-order
`•l'IIMll'\' nturons within the br.iinslt'm lligeminal nuclei.
`I 't11:or11rolled studies of retrogasse1i:ln rhiz0tom_v of the
`1ri!,!1·111in:il gnnglia hm·e been positive for 1he relief of mi(cid:173)
`j.!l'ainl· 12). Anticlromic or local mrdmnical stimulation ol
`-.·11s111~· ncr\'e endings is known to c:iuse vasodllatation
`in p,·dpht'n'll ,·es.~els \'ia the release of vasonc1ive mnteri(cid:173)
`:d~ ~11l·h as substanct! P :JIJ(.l calci ton in gene-related pep-
`1ide (CGRP) (3.4). This vasomotor t!ffecl of the sensory
`11,·r'll·.~ in lhc periphery appears 10 ha\'e a coun1erpa11 in
`1h,· re1't'brnl circulation with 1he tdgeminal system. The
`liht·1-s :ind the cell bodies contain a number or messengt'1·s,
`h111 CGRP is the one mosl f1"1:quently e,1,;pressed (5). More(cid:173)
`'"•·•: CGRP, and CGRP rt!lt'ased from pelivascular nen·~
`in the mt'ninges, has been conclusively demonstrated e.,(cid:173)
`pe1·1111en1nll,v to evoke clear vnsodilntion in pni11 produc(cid:173)
`ing i1111'olc:rnnial slructures (6-8). The neuronnatomic, ncu(cid:173)
`l'oJ'llll'~iulogic, surgical, nnd pharmacolog.ic evidence thus
`point Lo .1 kev role ror the trigeminocerebrovnsculnr sys(cid:173)
`,~.,, i11 thr trunsm ission of nocil·cptivc information lo the
`CNS during p1ima1y headache.
`C:GRP immunoreaclivit associa1eJ with inuncranial
`n:ssd$ was first shown in I 9R4 (9), and subsequently found
`10 originate in perikarya within lhc 1rigeminnl ganglia ol'
`all ,,µecics c.xamint·d, including humans ( I 0). CGRP is
`frcqu..-nil_v colocali~.ed in 11igeminal neurons with othn
`rirninllamm:uory sensory ncuropcptides and 1r.1~0.ic1ive
`~11bs1anc:cs. CCRP-contnining cells :ire the most prcl'nlent
`phc·n111ype in the trige.minal ganglion (5). Four sumccs of'
`
`cerebrovascular CGRP have been described: (i) the oph(cid:173)
`thalmic division of the trigeminal ganglion. to inne1vate
`the drcle of Willis irnd its branches by the misocili.11-:,·
`nerve; (ii) 1he maxillarv division. probably via an extraclu(cid:173)
`ml branch al the skull base 10 the internal caro1id ar1e1v;
`(iii) the internal carotid miniganglia, via the greater de~p
`petrosal nerve to disrribute in the internal carotid arter.'
`:ind disuibute proximally in its intracranial ramifications:
`(iv) in the 11pperce1vical dorsal rool g,mglia (C1 lo C3) to in(cid:173)
`nervaie the caudnl lh ircl of 1he basilar artery and the verte(cid:173)
`bral artery (6, I 0-18). The major cerebral a11e1ies (anterior,
`middle. and posterior cerebral arteries, Yencbral and basi(cid:173)
`lnr arteries) and pial Mtcrioles of the cortical surface are
`inrested with fine vn1icosed nen1e fibers that contain CGRP
`( 19). These nerve fibers arc present in the ad\'entilia and n1
`the adventitial-med ial border of the blood vessels. CGRP
`is colocaliied in these fibers with substance P (20.21 ). ncu(cid:173)
`rokinin A (22), PAC AP ( 1 \ ). NOS ( 11.23). amyl in (24), and
`nuciceptin (25).
`CGRP and its receptors are widel~ expres~d in pedph(cid:173)
`~ral tissues nnd Lhc central and peripheral nervous sys(cid:173)
`lems nnd I heir act ivaLion hns been linked 10 a diverse
`range of biological func1ions (4.26,27). CGRP is a 37-
`amino acid peptide that results from tissue-specific nl(cid:173)
`ternalive splicing of the calcitonin gene (28). II exists in
`two l'orms, ll'· anu ,1:1-CGRP (29), which show considerabie
`homology with nmylin and adnmomeduilin. CGRP recep(cid:173)
`tors have a heterodimclic nature comprising a G-protcin-
`1:oupled (Gs; aden:,,late 1:yclru.r) l'en•ptor (GPCR) known
`as the cnlcitonin receptor-like receptor (CLR) .ind a sin(cid:173)
`gfo transmembrane-spnnning protein known as receptor
`activity-modif_ving prott'in I (RAM P!) (30). RAMPI can
`also modulate the ph,11macolog:,, of other GPCRs su,h as
`the cnlci1onin n:ceptor (CTR), which when coe.xpressed
`with R.~MPI shows high affinity fnr amylin and CGRP
`(31.32). The receptors for the calcitonin-related peptides,
`CLR nnd CTR. arc in the same class B familv of GPCRs
`as the rt'1:t'pturs for secre1in, glucagon, vn~oactive in(cid:173)
`testin:il pol:,peptide (VIP) and parathyroid hormone. Until
`
`289
`
`

`

`-
`
`290
`
`The Migraines _
`
`_____ ______ -··--_ .....
`
`recently, the phnrmacolog_v nnd physiology or CGRP recep-
`101 could only be investiga1ed using uuncotcd versions of
`the CGRP peptide (CGRPB-37). Huweve1; nonpeptide an(cid:173)
`tngonists have now been developed (33), l'lnd 1hese have
`facilitated explnrntion of the physiologic role of CGRP. II
`is notewonh_, however. that marked species difference ·
`hDve been observed in the binding of the e antagonists
`that are important in the interpretation and selection of
`experimental and dinic:-al phannacologic models of pnl ho(cid:173)
`physiology (34).
`The wide distribution or CGRP and its receptors in
`CGRP the brain and cardiovascular system gives this
`peptide a potential for diverse ph_v~iologlc roles in nor(cid:173)
`mal nnd many palhologicol states (26,35,36), but Its
`most pronount.:ed action is probably 1ha1 of va.~o<lilata•
`lion (4,37). The dense innervation of the cerebral circu(cid:173)
`lation by trigeminal CGRP-conrnining uigerninal nerve
`fib!!rs (20,21) is central lo irs putative involvement in pri(cid:173)
`mary headaches. Trigeminal fibers mediate tlik1ta1ion or
`brain (19,38-40). meningeal and dural vessels (7,8,40-43),
`.ind int.:reases in cerebral blood llow (CBF) (44), yet ap•
`pe::ir lo have no ionic influence on CBF or metabolism
`(45). E.xperimcntall.v, these fibers relense CGRP when sim(cid:173)
`ulated electrically (44.46-49) or chemicall.v by capsniein
`(50-52) and when the trigeminornscular 1\.'nex is l!ig(cid:173)
`gcrcd (21.50.53). CGRP cleorly has n key runctional role
`(21,50,53,54) in I he uigem inovascular system and CGRP
`con1aining fibe1-s appear dinic.ill_v 10 be activated in pri(cid:173)
`lllDI)' headaches and in sti-oke (48,55-59). supporting its
`role in cranial sensorv functions. This re\"iew concentrates
`on the role or CGRP ~nd its receptors within I he intracra(cid:173)
`nial vasculaLure as targets forantimig:raine drugs; however,
`it is recognized that there is n widespread distribution of
`CGRP receptors within pain pathways in the tligeminal
`nuclei of the br:iinstem and that these could be activated bv
`CGRP released rrom the central tem1inals of the trigemi(cid:173)
`nnl nen:es and pla_,, a rnle in nociccptive 1ransmission from
`headnche pain-produdng ti~ues.
`
`NEUROPEPTIDE RELEASE IN
`PRIMARY HEADACHES
`
`The role or 1he sensory n:.-1Yes around the intracranial 1·es•
`sels in piimary hendaches has been l'luddated b_v annly(cid:173)
`sis or neurotransmiuer release in man: Actirntion of lhc
`trig.eminal ganglion rei.ulled in unilateral blood llow i11-
`crenses, CGRP ::incl substance P 1-elease, ::ind facial nushing
`on lhe side of stimulation (46).
`
`Migraine
`Thl!re are both va cular and neurogenic componen ts 10
`migraine a11acks (55). Many consider that the disonler is
`caused by mutations in a calcium-t.:hannel gene rendering
`
`) TABLE 31-1 Overview of Changes in Perivascular
`Neuropeptide levels OccuHing in
`Acute Attacks of Primary Headache
`Disorders
`
`NPY
`
`VIP
`
`:!:O
`:!: O
`±0
`:::0
`±0
`
`±0
`:!:O
`±0
`
`f
`
`Substance
`p
`
`CGRP
`
`±0
`±0
`±0
`±0
`±0
`
`r
`t
`t
`
`1
`
`Migraine without aura
`Migraine wit!, aura
`Trigeminal neuralgia
`Cluster headache
`Chronic paroxysmal
`headache
`
`.:::0, no change from before headache
`I significant Increase ,n neuropeptide to•el
`
`neurons linstab!c and capable of initiating a migraine at(cid:173)
`tack. The evidence for c:ilcium-t.:hann I involvemenl. hnw(cid:173)
`iiver, remains best for a relatively r:1re migraine variant,
`familial hcmiplcgic migraine (60). It has been proposed
`that as a result or 1his instability, the tJigeminovascu(cid:173)
`lar s.vs1 m becomes activated during the init iaLin~ events
`in migraine pathophysiology, resulLing in an amidromic
`release of CGRP, ,•asodil.ilation of pain-producing intra(cid:173)
`cranial blood vessels, and activation of second-order sen(cid:173)
`sory· neurons in the 11igemi nnl nucleus cnudalis wilh sub(cid:173)
`sequent perception of pain. Early clinical studk·s showed
`that sen~ur:,, neuropeplides are released and cnn be mea(cid:173)
`sured in the jugular 1·ein when the 11igeminal ganglion
`is stimulated drning lesioning of the lligeminnl ganglia
`for the lre,1t111enl of u·igeminal neuralgia ((cid:157) 6). This ob(cid:173)
`se111ation led to the hypathesis that neuronal messenger
`. molecules (neuropeptides} associuted with the autonomic
`:ind sensory ni:n·es ((cid:157) 6> may be similarly relea~ed during
`mig-raine.
`The cranial ,·enous outllow rrom the external jugu(cid:173)
`lar Yein (Tahle 31-1) was therefore analyzed for markm;
`of sympathetic (neuropcp!ide Y [NPY]), par.i~_vmpnlhetic
`(VIP), and sensory (CGRP and substance P) nern:s drns
`ing migraine headache. No changes were obst.:n-ed in the
`levels of N PY, VIP, or subsi.ince P. but a marh•d i111.:re.1se
`in CGRP was nbse1ved during migraine lu~ad:iche CGRP
`release was nh:erve<.I in patients with attacks of mi!:,'1Uinc
`with :,ur.i and those without aum. Two individuals with
`facial :1L1tonomic s_\'mptoms simil::!r 10 those seen in clus(cid:173)
`ler head od,e kg .. nasal congestion :111d rhino1·d1l':l), also
`showed increaset.l levd · uf VIP suggesting 1he ntlclitional
`inmhemcm of the parasympnthetic ~vstem in 1hese two
`individuals (56).
`The appan:1111.v selecli~e rdt:as~· or CGRP mlher 1han
`subst:incc P has been a point ur consider,1bll' discus(cid:173)
`sion. Sen ·01)' lrigcminal C fibers aris~• fr-om neurons in
`the 1rige111inal ganglia in which CGRP .ind suhslance
`P arc colocaliz~•d. where:is senso1v A8 libe1-s :iiise from
`
`

`

`11igeminal neurons containing predominantly CGRP with
`!!lutamate ( 10. 15, 16,61 ). The detection of CGRP in the ve(cid:173)
`~1ous effluent ·blood may simply reOec1 a greater density
`of innerva1 ion of the cerebral circulation or could rellecl
`differential release from C-fiber pools or preferential ac-
`1i,-ation of M- over C-liber populations. Regardless of its
`(ll"igin, CGRP released in the trigeminovasculnturc medi(cid:173)
`:ll~S prolonged vasodilata1ion of these pain-produdng in(cid:173)
`tracranial blood vessels. The initial clinical observations
`h:m: subsequendy heen conlirmed (48,62). Additional
`,•ddence supporting a role for CGRP in migraine headache
`.:amc from the pivotal observation that (lfter dosing the
`:i-HT1s110 agonisl (lntimigraine compound sumatriptan.
`the plasma levels of CGRP re1umed to normal concomi-
`1.1111 w11h successful amelioration of the headache (48).
`;;.HT1s110 receptors are expressed on trigeminal ganglion
`,·dis of man (63) and guinea pig (64) and on human
`1rigcminal sensory fibers (65,66), thereb~· providing sites
`lur presynaptic inhibi1ion of CGRP release from 1rigeminal
`,-.:nsoty netve te1minals. IL has ~en proposed from stud•
`il-s in 11igeminal neurons lhat this sumatriptan-mediaud
`inhibition of CGRP release is
`through a prolonged
`5-HT,o rec:eptor-mediated inc1-e.ise in inlracdlular cnl(cid:173)
`dum (67,68).
`
`Cluster Headache
`
`Cluster headache is a well-described. dear-cut clinical
`syndrome. Patients \\/ilh episodic cluster headache. ful(cid:173)
`tilling the cri1eri.i of the lmema1ional Headache Socidy
`11 HS). were examined during acute spontaneous auacks
`, ,r headache co delermine the lorn I cranial release of neu(cid:173)
`ropep1ides (57). Durin2 the anacks. 1he blood levels of
`bo1h CGRP and VIP we;-e markedly raised. although 1here
`\\•.ts no change in NPV or substance P (see Table 3 I- I).
`Tremment wi1h oxygen or subcutanc:ous sumatriplan
`:1borled the pain and normalized the CGRP levels (57).
`The linding of elevated levels of both CGRP and VIP dur(cid:173)
`ing a11acks suggesrs 1ha1 thc:re is actl\·ation of a brain(cid:173)
`stem renex. the afferent arc of which is 1he ttigeminal
`nerve and 1he efferent the cmnial parasympathetic outflow
`rrom cranial nerve VII (47,69.70). Indeed. ii w.is panicu(cid:173)
`larl_v noteworthy 1ha1 VIP release was detected in all sub(cid:173)
`jt'Cts in line with 1heir ex1racranial focial p.irasvmpathetic
`symptoms.
`The results in idiopathic headaches are in excellent
`agreemen1 with those of others. who have shown that
`CGRP levels are elevated during 11itroglyce1ine-elici1ed at(cid:173)
`tacks of cluster head(lche (57,71.72) and related 10 the
`intensi~· of the headache pain. There was no altera1ion
`in substance P levels. lntereslingl_v. only when !he sub(cid:173)
`jects were in an active pe1iod was nilroglyce1ine uble 10
`elicit an auack of cluster headache (72), suggesting 1hat
`the trigemino\'asrnlar ~.vstem maybe h_vperreac1ive at 1his
`lime.
`
`_ _ c_(!RP lnvolvem!:!!_t in Migraines
`
`291
`
`Trigeminal Neuralgia
`
`No differences have been found in the resting levels or sen(cid:173)
`sory neuropcptides between normal individuals and sub(cid:173)
`jects with trigeminal neuralgia (46). ln contrast, stimula(cid:173)
`tion of the trigeminal ganglion during thcrmocoagulation
`caused a marked increase in the blood levds of CGRP and
`substance P th(lt was associ(l(ed with unilateral facial Oush(cid:173)
`ing. After cessation of the stimulation. the peptide levels
`rel urned toward no,mal levels. Other studies of an unsta(cid:173)
`ble trigeminal system in which activation of a facial trigger
`point evoked pain that was associated with rhinorrhea, fu •
`i:ial Oushing. and elevnte<l levels of CGRP have also high(cid:173)
`lighted 1he complex interplay between vascular and pain
`biology responses to ncuronally derived vasoactive pep(cid:173)
`tides such as CGRP in the cranial vasculature (73).
`
`Chronic Paroxysmal Hemicrania
`
`Chronic paroxysmal hemic:rania (CPH) is a rare syndrome
`that is denned bv !he IHS operational diagnostic criteria as
`frequent short-lasting anacks of unilateral pain usually in
`!ht' urbi1a l, supraorbital. or temporal regions 1hat may last
`for 2 10 45 minutes (auack frequency, often five or mo1-e
`.:ach day). The pain is associated with prominent auto(cid:173)
`nomic symptoms such as conjunctiva! injection, lactima(cid:173)
`tion. nasal congestion, rhinorrhea, ptosis. or evelid edema.
`According to the diagnostic criteria. lhe allacks should set(cid:173)
`tle rapidly on treatment with indornethacin. In one such
`case of CPH. it was obse1Yed that, during pain, the CGRP
`lc:vel rose 3 limes compared 10 the level while 1he sub(cid:173)
`ject \\'as on indomethacin. The VIP lerel increased 4 times
`during an attack and nom1aliied with inc.lumclhacin trc:al(cid:173)
`ment (74). The case repo11 and 1he accompanying data
`show that auacks of CPH are characterized bv acriration
`of both sensory and parasympathetic cranial ~erve fibers.
`The ch(lnges obse,,·ed in CGRP and VIP levels dming CPH
`sugg·esl 1hal some (lspccts of i1s pathoph_vsiology mn_v re(cid:173)
`semble thost> of cluster headache.
`
`RESPONSES TO CGRP
`
`CGRP is (I potent cerebral ,-asodilator in all species stud(cid:173)
`ied lo date ( 19). The relative potency of different forms
`of CGRP varies m:ross sped.:s and so care is need in the
`in1erprem1ion and extrapolation or data. In human cere(cid:173)
`hral nneiies. the maximum responses to CGRP. substance
`P. and nt>urokinin A are similm: but CGRP induces re(cid:173)
`la.'iatlons at 100 10 1,000 limes lower concentrations. In
`general, CGRP is the most potent known vasoactive con(cid:173)
`sliluenl of 1rigeminovasc11lar nel\•es, hy far superseding
`substance P. neurokinin A, PACAP, amylin. galanin, .ind
`dynorphinc in cffic.,c_v and potency (Table 31-2). In addi(cid:173)
`tion. CGRP is abolll 25-fold more potent as a vasodilatorof
`
`

`

`.......
`
`292
`
`The Migraines
`
`~i TABLE 31 -2 Potency (pEC 50 ; pD 2l and Efficacy (Em••) of Neuronal Messengers
`Found in the Trigeminal Ganglion of CMA and MMA
`
`CGRP
`Substance P
`Neurakinin A
`PACAP•
`VIP
`PHM
`Amy/in
`Helaspectin'
`Nocicaptin
`Dynorphin
`Galanin
`
`Em••
`
`85-100%
`60-70%
`43--81%
`30%
`60-e0%
`634!7%
`82%
`50%
`0%
`0%
`0%
`
`MMA
`plJi
`
`8.7 ± 0.2
`9.6 ± 0.2
`7.6 ± 0.4
`
`7.5 ± 0.2
`6.8 ± 0.1
`
`MMARel
`Pot vs SP
`
`0.12
`1
`0.01
`
`0.01
`0.002
`
`CMA
`plJi
`
`10.1 ± 0.2
`8.7 ± 0.2
`7.7 ± 0.3
`7.7 ± 0.9
`8.6 ± 0.2
`7.2 ± 0.2
`8.3 ± 0.2
`8.8 ± 0.6
`
`CMA Rel
`Pot vs SP
`
`25
`l
`0.1
`0.1
`0.8
`0.03
`0.4
`1.3
`
`'CaL
`E.,... value, variation In different human swdies.
`P[½. from cited human studies lsee IDMI).
`Relative potency as compared 101he value of substance P ISPI sel as unity.
`
`cerebral as compared 10 other cranial a11eries (39,75,76).
`lmmunohistochemical ;ind autoradiograph ic studies (77)
`and the modeling of receptor dynamics outlined by Black
`and Leff (78) indicate 1h01 this phenomenon probably re(cid:173)
`llects lhe existence of a higher density of CGRP receplors
`in cerebra] as compared to oL.l,1:r arteries.
`Phannacologic s1udies have shown tha1 the rel:1.~anL
`(vasodilator) effec1sofCGRP are probably smooth muscle(cid:173)
`mecliatecl; lhey per hi evl!n ufler removal of lhe em.lo1he(cid:173)
`lium. Relaxa1ion is accompanied by increased adenvlate
`cyclnse activit_v (79) commensurate wi1h the Gs coupling
`of the receptor. Both relaxation and second-messenier ef(cid:173)
`fec1s were blocked b.v a CGRP ancagonisl (51 ). The ef(cid:173)
`fects of CGRP have been studied c.~tensivel:v using pinl
`blood vessels in situ. The d::t1t1 showed 1h;it CGRP induce
`a greater dihmnion of pial anerioles than substance P
`(21 ). The pial arteriolnr responses aflera single 11pplicntion
`of CGRP were usl:iined for several minutes, particularly
`at hiirh concentrations (21,53). To understand 1he role of
`CGRP released from perivnscular nen1es relacive 10 circu(cid:173)
`lating CGRP, 1he pressuri:1.ed midclle cerebral artery (MCA)
`method with ra1 blood vessels has been used 10 inves1l(cid:173)
`g:11e the relati e contribution of endothelial and smooth
`muscle cells 10 \'«scular lone. The effects of luminallv
`and abluminally applied a- ancl /1-CGRP, a<lrenomcdulli~.
`nnd amylin on blood vessel diameter were compared to
`the resting condition. Of all substances tes1ed. on! nhlu(cid:173)
`minally administered a - ,ind ,B-CGRP showe::d signifirnnl
`cJj(:l!or:v effectS Lhal were proven Ltsing a selective CGRP
`antagonist to be mediated through CGRP receptors (go).
`This finding suggesls 11ml under normal in vivo cont.lit ions,
`circulating CGRP may be restric1ed from reaching its re(cid:173)
`ceptors in 1hc smooth muscle by an endothelial cell bar(cid:173)
`rier and thus make liule t·omribution lo cranial vascular
`tone.
`
`A recent stud. in humans using SPECT 10 determine
`regional CBF (rCBF) revealed that systemic infosion of
`CGRP had minor effects on rCBF (8 1,82). Transcranial
`Doppler used in parallel Lo determine blood flux velocity
`in the MCA showed a reduction during the CGRP in fu(cid:173)
`sion, suggesting that CGRP had dilated the MCA in vivo.
`These findings agree well with studies on the effects of
`CGRP stuwes on regional CBF in rats. guinea pigs. and
`rabbits where univ minor effects were obsen•t'd (83-85).
`~el differ some, hat from the lack of activiiy observed
`when CGRP was adminis1ercd inlralumenallv nl low con(cid:173)
`centrations in the pressuli:ted MCA nssa_v. It is not kno11,n
`how 1he doses of exogenous CGRP that nre used lo e\'oke
`rasodilalation intravenously relate lo the concentrations
`of CG RP that when release-cl from peri\·ascular seusory
`nerves produce equivalent dilator effec ts, but ii is conceiv(cid:173)
`able !hat 1hey arc much higher. Circulating levels of CGRP
`are normally relatively low and cont,ibute li ule lo cranial
`vasomotor tone. High e.~ogenous intravenous CGRP doses
`probably drive smooth muscle CGRP receptor occupancy
`and consequenl va odil,11a1ion ·imply through mass ;1c-
`1ion. In pathophysiologic condition , when the endo1he(cid:173)
`lial barrier is significantly breached or pcrmcabilized by
`proinllammatory peptide · such ns substance P, circula1-
`ing CGRP can reach its smooth muscle receptors ea.silv 10
`enhance vasodilator effects.
`To assess the inlluen e of I he trigeminal system on cere(cid:173)
`brovascu lar tone, a serit's of e.xperime n1al s1ud ies exam(cid:173)
`ined the consequences of chronic surgical division of the
`l1igeminal nerve in cals. This manipulation did nol mod(cid:173)
`ify local CBF, brain glucose utiliz:i1ion. or the magni1ude of
`the a11eriolar responses 10 perivascular microapplicntion
`of either \·asoconstric1or or vasodilalor agents (45), sug(cid:173)
`gesting that CGRP und other uigeminul senlior~ peptilles
`m·e noc involved in Sl'lling basal cl!rebrova;;cular lone. In
`
`

`

`r
`
`CGRP Involvement in Migraines
`
`293
`
`FIGURE 31-1. Schematic illus(cid:173)
`LraLlon or 1he 1rigeminovascular
`ren..-.( as shuw11 hy e~perime111S
`in 1hc c.1t (21,52,53). lrrespcc1ivc
`which YOSoconstrictor that w:is
`Ltsed the cortex anerioles dilated
`back lo original cli:imtrer in I he
`sen.~01)' inner,,ated vessel within
`I minute, but it w:is malied!y
`prolonged
`in
`the 1rigeminal
`(CGRP was
`lesioned animal
`deple1cd from these vessels as
`shown both bv
`immunocv10-
`d1emis1rv and . rodloimrnuno(cid:173)
`:1ssay).
`·
`
`contrast lo these findings, and in line with the hypothesis
`that CGRP relea ed locally from pe1;vascular nen·es can
`:iffcct cerebral vessel calibers, stimulation or the trigemi(cid:173)
`nal nerve or its branches results in CBF increases that can
`bt: blocked by CGRP antagonists (44,48.86.87) .
`It has been proposed that the 1.:erebrova cular 11igemi(cid:173)
`nal neuronal system, in which CGRP is che most potent
`msoactive constituent. has a protective role in counter(cid:173)
`acting excessive cerebral vasoconsuiction (21 ). Ct remains
`unclear whether 1his CGRP-mediated effect is a local re(cid:173)
`sponse, resu lting from dfrect mechanical stimulation of
`sensory nerve i:ndings, or whether ii forms part of a re(cid:173)
`llex arc with the uigeminal nerve constituting the affer(cid:173)
`ent or efferent limb (Fig. 31-1 ). II is noteworthy, however.
`that trigeminal lesions, which inlerfere with neuronal•
`mediated v:iscular compensatory responses, hnve been
`!>hown e:1pelimcnu11ly to prolong the duration of Lhe cere(cid:173)
`bral a11eriolar vasoconstriction induced bv noradrenalin,
`prostaglnndin F2a, barium chloride, alkaline pH, and
`hlood without aheling the durntion of vasodilatory re(cid:173)
`sponses (21,53 ).
`Under some circumstances. there could be consider.ible
`pathologic significance to a ccrebroprolective mechanism,
`sul'i1 as the trigeminovascular rellex. Preclinical studies
`suggest that CGRP is depleted from cerebral \'Cssds in sub(cid:173)
`arachnoid hemorrhage (SAH) (88) and that CGRP levels
`in cranial venous blood and in CSF correlate with the dc(cid:173)
`~ree of cerebrovascular constriction in SAH as mt'asured
`with lranscranial Doppler (58,89). In 1he clinic it h:is been
`argued that CGRP cannot he detected in cerebral blood
`\'essels or patients that have died from SAH (89), because
`the peptide has nlrcady been selectively released in on un(cid:173)
`successful attempt to maintain adequate levels of blood
`now. In the same patients, howe\'er, Ct'rebrov.iseular lev-
`
`els of other perivascular vasoactive peptides were close to
`the le,·els found ln normal subjects. Clinical studies have
`hown 1ha1 adminis-1ra1ion of exogenous CGRP 10 patients
`with s rmptoma1ic vasospasm can be u ed to reverse the
`constriction, providing blood pressure is carefull)• con(cid:173)
`trolled (59). Experimental studies in primates have also
`shown that CGRP can prevent cerebral vasospasm after an
`c.,perimentnl SAH (91 ). Although these s1udies emphasize
`a l'asomotor role for CGRP in the trigcminocerebrovas(cid:173)
`cular system, it should not be to the e.~dusion or its in(cid:173)
`volvement in cranial nociception; intense head p.iin often
`accompanies SAH.
`The role of the trigeminovascular nen,ous sys<em can
`be conceptualized as the coun terp;m 10 the perivascular
`s,vmpathetic nervous s.vstcm that mediates ccrebrovascu(cid:173)
`lar constriction. The f1Jnc1ion of the s~•mpathetic fibers in
`this \·asoconsnictor system is to attenuare or prevent ex(cid:173)
`cessive \'asodilatation in situations such as extreme hyper(cid:173)
`tension (92) rather than reduce CBF. Tn contrast, the Fune(cid:173)
`lion of the vasodilator trigeminal system is not to increase
`CBF. but rather 10 allenuate excessive cerebral vasocon(cid:173)
`·triclion. Activation of pro1ective auronomic cerebrovas(cid:173)
`cular renex responses is central Lo the maintenance of CNS
`function when extremes or cerebral perfusion threaten
`neuronal su rviva l.
`
`CGRP AND ITS RECEPTOR
`
`CGRP is present in two forms, a- and ,B-CGRP. Cl'·CGRP
`is produced by tissue- ·pecific alternative mRNA splicing
`of the calcitonin gene and ,B-CGRP is formed from a
`separate CCRP gene (28,29,93,94). CGRP and its recep(cid:173)
`tors are widely expressed centrally and in the periphery.
`
`

`

`294
`
`The Migraines ·--·-------- - ·-
`
`·- -·-- -·------- ·----- -·-
`
`MMA
`PA
`Ii
`. ~--- .
`',1:,rr?-·~✓-~ .... :-:-~
`•
`lei ·>
`
`l,
`___ ,,
`
`MMA
`
`PA
`
`Ulex
`
`1m-
`
`le
`
`1 r, .-;-:-_r, Ii 1 -:-~ -::.-
`~. ,- --..
`-·. ~~I~~~~;;::_·-:i _ .,':,~--
`
`Actin
`
`GALA
`
`RAMP1
`
`RAMP2
`
`RAMP3
`
`FIGURE 31-2. Cellular expression of CGRP-RCPs in human middle: meningeal IMMAI, pial (PAI. and
`middle cerebral ;irlcrv (MC.'\). CRLR and R.AMP2-likc immuno,~cli\"e material (ir) were ubundanL in
`smooth muscle and in endo1lielial cells. wher.-as RAMP 1-ir and R.O.MP3-ir ,w,1.' panieul::11fr e.~pres.sed
`in smomh muscle L'ells (76).
`
`Cloning efforts have revealed 1he heterodimeric molecular
`nature of CGRP recep101'S (Fig. 31-2) (95). CGRP recepto1'S
`compri e the calcitonin-reccptor-like reccp1or (CRLR)
`coexpressed with a rccep1or ac1ivi1y-modifying protein
`(RAMP). RAMPs are relatively small proteins (148 10 175
`amino acids) containing a single membrnn spanning do(cid:173)
`main, a lnrge extracellular domain, and a short cytoplasm
`domain (30,96). Coexpression of CRLR wilh RAMP I forms
`CGRP receptors. whereas coexpression with RAMP2 or
`RAM P3 form.~ receptoi'S for adrenomedullin. CRLR and
`1he CTR share 57% sequence on tht' umino acid level and
`are seven-transmembrane domain GPCR linked lo aden(cid:173)
`vlate c\'clase (Gs). RAMP] can also modulate 1he pham1a(cid:173)
`~ulog_v· of 01her GPCRs such as 1he CTR chat, when coe.~(cid:173)
`pressed with RAMP I. shows high affinit.v for amylin and
`CGRP (32).
`Three biolpgirnl rum:tions have been dd-ined for
`RAMPs: (i) They enable expression of CRLR on the cell
`surface and 1hereby determine the rcllllil·c affinity of 1his
`rix:ep1or for CGRP and :idrenomedullin (96). (ii) CRLR
`intema)il'.ation following CGRP slimul:11ion has been
`shown 10 occur together with RAMP I, and both pro(cid:173)
`teins are targeted to 1he prnkin degrada1ion pathway
`(97). Although the receptors resulting from coexpression
`of CRLR with either RAMP! or RAMP2/3 are fu nction(cid:173)
`allv di tinct, CGRP and adrenomedullin displayed some
`cross-reiictivity for the opposite recep{or (30). (iii) RAMP
`proteins h,we, in addition, been shown to mo<luliite the
`pharmacology of the calcitonin receptor, which in combi-
`
`nation with RAMPl or RAMP3. hinds amvlin with hieh
`arfinicv (31,98).
`·
`-
`II has been proposed that functional CGRP recep101'S
`may require onolher iiccessory protein in addilfon to tile
`RAMP I. This hus been rennet! the 1-el·eplor 1:umponenl
`protein (RCP) (99). Using cell lines th.ii express amisense
`RCP mRNA, it was demonstrated that the abilit~· of CGRP
`to ~timulate l'_vclic adenosine monophosphate production
`was attenuated , ahhough l?.•t-CGRP binding was una