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R E V I E W S
Migraine is a public health problem ofgreat impact on
both the patient and society. The overall migraine
prevalence in western countries is 6–8% in men and
15–25% in women.It has been calculated that about
5% ofthe general population have at least 18 days of
migraine per year,and that at least 1% — that is,more
than 2.5 million people in North America — have at
least one day ofmigraine per week.Severe migraine is
rated as one ofthe most disabling chronic disorders.
The annual cost ofmigraine-related lost productivity is
Migraine attacks are typically characterized by
unilateral and pulsating severe headache,lasting 4–72
hours,and are often accompanied by nausea,phono-
and photophobia (migraine without aura;MO).In at
least 20% ofpatients,the attacks are preceded by tran-
sient (usually less than 60 min duration) neurological
symptoms (migraine with aura;MA).Auras are most
frequently visual, but can involve other senses, or
occasionally cause motor or speech deficits.
Migraine has a strong (up to 50%) genetic compo-
nent,which is higher in MA than MO,with a probable
multifactorial POLYGENIC inheritance.Genetic load can be
seen as determining an inherent migraine threshold
that is modulated by external and internal factors
(migraine triggers).Although several susceptibility loci
have been reported in chromosomes 1q,4q24,Xq24-28
and 19p13 (REF.1),causative genes have not yet been
identified, except for familial hemiplegic migraine
(FHM) — a rare,autosomal dominant subtype ofMA.
Here we review recent experimental evidence mainly
from brain imaging and neurophysiological studies
that, despite leaving many open questions, have
advanced our understanding of migraine towards a
unifying pathophysiological hypothesis to explain this
disease.Convincing mechanistic explanations for some
ofthe migraine symptoms have been discovered.So,
activation ofthe trigeminovascular system (TGVS) is
thought to be responsible for the pain itself,and cortical
spreading depression (CSD) seems to underlie the aura
symptoms.Important questions that remain include
the primary cause ofmigraine,leading to activation of
the TGVS,and the mechanisms ofpain generation after
its activation.We will discuss these questions in the
context of the discovery that Cav2.1 Ca2+channel
dysfunction causes FHM.
Neurobiology of migraine headache
We will discuss recent advances in the neurobiology of
migraine headache in the framework ofthe established
mechanisms that are briefly summarized here and
illustrated in FIG.1(see REFS 2–4for reviews).
Within the skull, pain sensitivity is primarily
restricted to the meningeal blood vessels, which are
densely innervated by nociceptive sensory afferent fibres
ofthe ophthalmic division ofthe trigeminal nerve.It is
generally recognized that thedevelopmentofmigraine
headache depends on the activation ofthese afferents.
In different animal models,including non-human
primates,activation ofthe meningeal trigeminovascular
NEUROBIOLOGY OF MIGRAINE
Daniela Pietrobon* and Jörg Striessnig‡
Migraine — an episodic headache — affects more than 10% of the general population. Despite
recent progress, drug therapy for preventing and treating migraine remains unsatisfactory for
many patients. One problem that slows the development of new therapeutic approaches is our
limited understanding of migraine neurobiology. Activation of the trigeminovascular system is a
central step in the development of migraine. However, two main issues remain incompletely
understood: the primary cause of migraine, leading to activation of the trigeminovascular system,
and the mechanisms of pain generation after its activation.
A characteristic controlled by
different genes,each ofwhich
has only a small role in the
Padova,via G.Colombo 3,
Correspondence to D.P.
NATURE REVIEWS |NEUROSCIENCE
VOLUME 4 |MAY 2003 |3 8 7
R E V I E W S
The exit offluid from a blood
An area oflost vision that is
surrounded by an area ofless
depressed or normal vision.
neuropeptides that are released by trigeminal ganglion
stimulation produce vasodilation ofthe meningeal vessels
(mainly due to CGRP),plasma EXTRAVASATIONand mast cell
degranulationwith secretion ofother proinflammatory
substances in the dura (neurogenic inflammation).
Trigeminal nerve activation also leads to vasodilation of
meningeal blood vessels through activation ofa parasym-
pathetic reflex at the level of the superior salivatory
Evidence that activation of the TGVS occurs in
humans during migraine is provided by the increased
level of CGRP that is found in both the external and
internal jugular blood during migraine attacks6,7,and its
return to normal levels after treatment with sumatriptan
and subsequent headache relief8.
The two main open issues in the neurobiology of
migraine headache are,first,the primary cause ofthe
migraine headache — that is,the mechanism ofactiva-
tion of the TGVS — and, second, the mechanism of
pain generation after activation ofthe TGVS.
Primary cause of the migraine headache
According to the once widely accepted ‘vascular theory
ofmigraine’,the symptoms ofmigraine aura are caused
by transient ischaemia that is induced by vasoconstric-
tion,and the headache arises from rebound abnormal
vasodilation of intracranial arteries and consequent
mechanical activation ofperivascular sensory fibres.
However,functional brain imaging during MA attacks
shows spreading cortical hyperaemia that is followed by
oligaemia, which outlasts the aura symptoms and
extends into the headache phase9.Moreover,there is no
clear evidence for a significant increase in the diameter
ofthe middle cerebral artery during migraine attacks10,
and a recent study clearly shows that migraine can be
induced without dilation ofthis artery11.These findings
make the vascular theory untenable for most migraine
patients4.It is now generally recognized that the pri-
mary cause ofthe migraine headache lies in the brain,
but its cellular and molecular mechanisms remain
largely unknown.Recent findings point to two main
mechanisms:CSD and a brainstem generator.
Neurobiology ofmigraine aura and CSD.In 1941,the
neuropsychologist Karl Lashley analysed the progression
of his own visual aura,consisting of a SCOTOMA with a
scintillating border drifting slowly across the visual field
(FIG.2a).He postulated that the scotoma resulted from a
region ofdepressed neural activity in the visual cerebral
cortex,and that the scintillations resulted from a border-
ing region ofintense cortical excitation.He calculated
that the neural disturbance propagated slowly across the
cortex (at about 3 mm min-1).A few years later,an elec-
trophysiological correlate was reported by Leao in the
rabbit cerebral cortex12and termed CSD.In animals,
CSD can be triggered by focal stimulation (electrical,
mechanical or with high K+) ofthe cerebral cortex,more
readily in the occipital region than other regions.It is
characterized by a slowly propagating wave (2–6 mm
min-1) ofsustained strong neuronal depolarization that
generates a transient (in the order ofseconds),intense
afferents leads to activation ofsecond-order dorsal horn
neurons in the trigeminal nucleus pars caudalis (TNC)
and the two uppermost divisions ofthe cervical spinal
cord.Impulses are then carried rostrally to brain struc-
tures that are involved in the perception ofpain,includ-
ing several thalamic nuclei and the ventrolateral area of
the caudal periaqueductal grey region (PAG).The PAG
is involved in craniovascular pain not only through
ascending projections to the thalamus,but also through
descending modulation (mainly inhibitory) ofnocicep-
tive afferent information5.Activation ofthe TGVS also
leads to release ofvasoactive neuropeptides contained in
their peripheral nerve endings,especially the calcitonin
gene-related peptide (CGRP).In animal studies,the
Figure 1 |Neuronal pathways involved in trigeminovascular activation and pain
processing. IV, fourth ventricle; ACh, acetylcholine; CGRP, calcitonin gene-related peptide; LC,
locus coeruleus; PAG, periaqueductal grey region; MRN, magnus raphe nucleus; NKA, neurokinin
A; NO, nitric oxide; SP, substance P; SPG, superior sphenopalatine ganglion; SSN, superior
salivatory nucleus; TG, trigeminal ganglion; TNC, trigeminal nucleus pars caudalis; VIP, vasoactive
3 8 8 |MAY 2003 |VOLUME 4
R E V I E W S
spike activity as it progresses into the tissue,followed by
neural suppression that can last for minutes13.The depo-
larization phase is associated with an increase in regional
cerebral blood flow (rCBF), whereas the phase of
reduced neural activity is associated with a reduction in
rCBF13.The similarities between migraine visual aura
and CSD led to the hypothesis that CSD was responsible
for the aura9,13.This hypothesis was questioned because
electroencephalographic recordings during surgery did
not show CSD in humans.Whereas it is clear that CSD is
more difficult to elicit in human than in rodent cortex,
changes in several parameters that are similar to those
typical ofCSD in animals were measured in the brain of
a patient with head trauma14.Moreover,transient elec-
trocorticogram suppressions that are consistent with
CSD were recently measured in the injured neocortex of
several patients15.CSD was induced and direct current
(DC) shifts were also measured in non-human primates,
in which,however,no prolonged hypoperfusion was
observed after the focal hyperaemia16.
Recently,blood oxygenation level-dependent func-
tional magnetic resonance imaging (BOLD fMRI)
showed CSD-typical cerebrovascular changes in the
cortex of migraineurs while experiencing a visual
aura17,18.A clear temporal correlation was established
between the initial features ofthe aura percept (scintil-
lations beginning in the paracentral left visual field) and
the initial increase in the mean BOLD signal,reflecting
cortical hyperaemia17. The subsequent decrease in
BOLD was temporally correlated with the scotoma that
followed the scintillations.The BOLD signal changes
developed first in the extrastriate cortex (area V3A),
contralateral to the visual changes. It then slowly
migrated (3.5 mm min-1) towards more anterior
regions of the visual cortex,representing peripheral
visual fields,in agreement with the progressive move-
ment ofthe scintillations and scotoma from the centre
ofvision towards the periphery (FIG.2b).
More direct evidence that CSD underlies visual aura
was obtained with MAGNETOENCEPHALOGRAPHY (MEG).
Slow changes ofthe cortical magnetic field,correspond-
ing to the DC potential changes that are produced by
the neuronal depolarization in CSD,were measured in
patients during a spontaneous or visually triggered
visual aura19.The DC MEG field shifts resembled those
previously measured during CSD moving across a
sulcus in animal models20.
The demonstration of cerebrovascular and mag-
netic field correlates ofCSD in migraineurs supports
the conclusion that visual aura arises from CSD.Auras
with motor or other sensory symptoms probably also
result from CSD-like events within primary motor or
CSD produces substantial changes in the composi-
tion ofthe extracellular fluid in the rat cortex21.Many
substances such as K+ions, protons, nitric oxide,
arachidonic acid and prostanglandins,the concentra-
tions ofwhich increase during CSD,can activate and/or
sensitize the meningeal trigeminovascular afferents22,23.
Recently, direct evidence was obtained that CSD,
induced by either a pinprick or electrical stimulation,
Figure 2 |Spreading suppression of cortical activation during migraine aura. a | Original
drawing by Lashley illustrating the progression of his visual aura over time, consisting of a scotoma
(within dashed line) and a scintillating border with typical fortifications. The cross indicates the
fixation point. b | Visual field defect of a patient studied with brain imaging. The fixation point
appears as a small white cross. The red arrow shows the overall direction of progression of the
visual percept. c | Reconstruction of the patient’s brain on the basis of anatomical data. The
posterior medial aspect of the occipital lobe is shown in an inflated cortex format. In this format, the
cortical sulci and gyri appear in darker and lighter grey, respectively, on a computationally inflated
surface. Signal changes over time are shown to the right. Each time course was recorded from one
in a sequence of voxels that were sampled along the primary visual cortex, from the posterior pole
to a more anterior location, as indicated by arrowheads. A similar blood oxygenation level-
dependent response was found within all of the extrastriate areas, differing only in the time of onset
of the magnetic resonance perturbations. The perturbations developed earlier in the foveal
representation, compared with more eccentric representations of retinotopic visual cortex. This
finding was consistent with the progression of the aura from central to peripheral eccentricities in
the corresponding visual field (b and d). d | The maps of retinotopic eccentricity from the same
subject as in b and c, acquired during interictal scans. As shown in the logo in the upper left, voxels
that show retinotopically specific activation in the fovea are coded in red (centred at 1.5°
eccentricity). Parafoveal eccentricities are shown in blue, and more peripheral eccentricities are
shown in green (centred at 3.8°and 10.3°, respectively). Modified, with permission, from REF.17
(2001) The National Academy of Sciences.
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challenges the idea that CSD induces migraine.Imaging
studies have also identified a few MA patients that
develop headache contralaterally to documented changes
in rCBF or preceding rCBF changes29,30.
Brainstem generator. An alternative view considers
migraine aura and headache as parallel rather than
sequential processes, and proposes that the primary
cause ofmigraine headache is an episodic dysfunction in
brainstem nuclei that are involved in the central control
ofnociception3,31.Two findings have been considered to
provide indirect support for this idea.First,placement of
electrodes in PAG for the treatment ofchronic pain can
produce migraine-like headaches in non-migraineurs32.
Second,rCBF increases in several areas ofthe dorsal ros-
tral brainstem during migraine attacks30,33,34.Although
the spatial resolution ofthe imaging techniques does not
allow the distinction ofmost brainstem nuclei,the foci of
maximum rCBF increase,as measured by PET,coincided
with the dorsal raphe nucleus and locus coeruleus in
patients with MO33,and with the red nucleus and sub-
stantia nigra in a patient with MA during a spontaneous
attack18.The red nucleus and the substantia nigra were
also the sites ofmaximum rCBF increase in MA and MO
patients studied with BOLD fMRI during visually trig-
gered migraine episodes30.Animal studies indicate that
these brainstem centres might be involved in the central
control ofnociception and,in particular,in descending
mechanisms ofpain inhibition30,35,36.Several observa-
tions have been considered to argue against the interpre-
tation that increased rCBF in the brainstem during
migraine attacks results just from pain perception or
from increased activity ofthe endogenous antinocicep-
tive system in response to pain.Increased rCBF in the
dorsal rostral brainstem persisted even 30 min after pain
relieffollowing treatment with sumatriptan33,34.In addi-
tion,the pattern ofrCBF increases in the brain differs in
migraine headache, cluster headache and head pain
induced by subcutaneous capsaicin in the forehead,even
though all ofthese headaches involve activation ofthe
first division ofthe trigeminal nerve37,38.On the basis of
these observations, it has been proposed that the
increased brainstem rCBF during migraine attacks might
indicate defective activity that would either trigger the
migraine headache (brainstem generator ofmigraine) or
contribute to central hyperexcitability of trigeminal
As the brainstem generator hypothesis provides no
clear answer to the crucial question ofhow the trigemi-
novascular afferents become activated as a consequence
ofbrainstem dysfunction,a permissive role ofdysfunc-
tional brainstem nuclei seems more likely4.A defect of
descending antinociceptive activity could result in
decreased inhibition of TNC neurons, making them
more susceptible to activation by the TGVS and to sensi-
tization.However,activation in brainstem nuclei that are
involved in the central control ofnociception was not
observed in all patients, at least in visually triggered
migraine30.Moreover, activation in the red nucleus and
substantia nigra was short lived and subsided before the
end ofaura symptoms in a spontaneous attack ofMA18.
can activate these afferents24.In the rat,transient,corti-
cally spreading hyperaemia during CSD was followed by
both sustained cortical oligaemia and dilation ofthe
middle meningeal artery.This dilation was abolished
after ipsilateral trigeminal or parasympathetic denerva-
tion.CSD also produced plasma protein extravasation
from dural blood vessels (but see REF.25) and increased
FOSexpression in caudal TNC neurons.Both effects were
abolished by trigeminal nerve section. However,
enhanced firing ofTNC or upper cervical spinal cord
neurons after CSD has not been directly demonstrated
yet25,26. Given that neurons activated by CSD might
represent a relatively small proportion ofcells,possible
explanations are intrinsic sample size limitations and/
or incorrect localization of single-cell electrophys-
iological recordings.Despite the lack ofdirect electro-
physiological evidence, the animal studies strongly
support the conclusion that CSD can activate the
meningeal afferents,and are consistent with the idea that
CSD is the primary event that induces a migraine attack.
As CSD underlies the aura, the fact that most
migraineurs do not experience an aura apparently con-
flicts with the idea ofCSD as a primary event.The possi-
bility that CSD also occurs in MO patients and causes
headache without giving rise to preceding aura symp-
toms,possibly because it originates in a clinically silent
area ofthe cerebral cortex,is neither proven nor excluded
by current evidence.A bilateral decrease in blood flow,
starting in visual association areas and spreading anteri-
orly,was measured in a patient with MO who was having
an attack during a positron emission tomography
(PET) scan27.Measurements ofrCBF in MO patients
after several hours from the onset ofheadache during
spontaneous attacks gave conflicting data:an average
reduced global rCBF was measured with PET28,whereas
no change in rCBF in the visual cortex was measured
with fMRI PERFUSION-WEIGHTED IMAGING29.In patients with
MA,the hypoperfusion slowly returns towards baseline
during the aura phase and the initial part of the
headache29,and patchy regions ofincreased rCBF some-
times develop after several hours13.So,an unchanged
average rCBF in the visual cortex ofpatients with MO
several hours after onset ofheadache does not rule out
development ofCSD in silent areas ofthe cortex.Note
that the studies mentioned above could all miss the ini-
tial phase ofhyperaemia during CSD because the time of
measurements fall well into the headache phase or might
fall in the time between PET scans.However,a recent
study that analysed visually triggered attacks in both MA
and MO patients showed hyperaemia in the occipital
cortex,independently ofwhether the headache was pre-
ceded by visual symptoms30.Moreover,bilateral hyper-
aemia in the occipital cortex, more widespread than
expected from the localized nature of the visual
symptoms,was measured in a patient with MA during a
In most patients with MA,the unilateral visual aura
is contralateral to the pain and precedes the headache,as
expected ifCSD activates the TGVS.However,the pres-
ence ofa small number ofMA patients with ipsilateral
visual aura and pain,or with aura after the headache,
A non-invasive technique that
allows the detection ofthe
changing magnetic fields that are
associated with brain activity.As
the magnetic fields ofthe brain
are very weak,extremely
sensitive magnetic detectors
known as superconducting
quantum interference devices,
which work at very low,
(–269 °C),are used to pick up
An immediate early gene that is
rapidly turned on when many
types ofneuron increase their
activity.It can therefore be used
to identify responsive neurons.
Imaging technique in which the
magnetic resonance signal is
intrinsically sensitive to the
presence and rate ofblood
perfusion.It commonly involves
the intravenous injection ofa
bolus ofa contrast agent,and the
subsequent imaging ofthe
changes in signal intensity as the
contrast agent first passes
through the brain.
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inhibition in MA,as determined by repetitive TMS41,43.
Controversial results regarding cortical hyperexcitability
have been obtained after TMS motor cortex stimulation45.
Recordings of evoked potentials or EVENT-RELATED
POTENTIALS also indicate altered cortical processing in
migraineurs. Interictal changes of evoked potentials
elicited by visual,auditory and somatosensory stimula-
tion have been reported in MA and MO,although with
some inconsistencies concerning changes in amplitude
and latency (see REF.43for review).An elevated negativity
of the initial component of the so-called CONTINGENT
NEGATIVE VARIATION(iCNV) was found in a large proportion
ofadult and juvenile MO patients46–49.Interestingly,such
a negativity is already elevated at early ages in children
with migraine49,indicating that it is probably not a conse-
quence of the disease.It is under debate whether the
enhanced negativity ofevoked potentials averaged from a
series ofrepetitive measurements is,at least in part,the
result ofdecreased habituation50.Habituation ofevoked
potentials — whereby their amplitudes decrease and
their latencies increase with repetitive stimulation — can
be shown in healthy subjects.By contrast,habituation to
repeated stimuli can be decreased or absent in patients
with MO or MA.For example,a habituation deficit has
been consistently shown for visual,auditory and somato-
sensory-evoked potentials,and for the P300 POTENTIALand
the iCNV43,51,52.Habituation ofresponses to olfactory and
auditory stimuli occurs more rapidly in cortical neurons
than in first- or second-order neurons53.It is therefore
possible that the observed habituation deficits reflect cor-
tical dysfunction and are consistent with cortical hyper-
excitability.Lack ofhabituation could contribute to the
enhanced susceptibility ofmany migraineurs to sensory
stimuli.Another consistent finding in migraineurs is a
higher intensity dependence ofauditory cortical evoked
potentials43,54,55,which might reflect hyperexcitability of
the auditory cortex.
Most interestingly,many of the described abnor-
malities of evoked potentials and their habituation
can return to normal during migraine attacks.
Normalization ofP300 latency habituation during MO
attacks was preceded by an increased habituation deficit
until the last measurement (about four days before the
attack)56.Increased iCNV negativity abruptly decreased
and the habituation deficit disappeared during an attack
with a tendency for iCNV negativity and habituation
deficit to reach a maximum the day before the attack43,57.
Parallel changes in the electroencephalographic (EEG)
power spectrum were observed58.These observations
support a phenomenon of‘neurophysiological period-
icity’58— periodic changes ofcortical excitability that
might lead to an attack when enhanced activation coin-
cides with other precipitating stimuli.This phenome-
non might also contribute to premonitory symptoms
such as changes in mood,vigilance and appetite up to
24 hours before the attacks.
A reduced preactivation level59ofsensory cortices
such that sensory stimuli do not reach the level for activa-
tion of habituation as a protective mechanism has
been proposed as an alternative explanation for the
habituation deficit in migraineurs59.Consistent with this
These observations seem inconsistent with a necessary
dysfunction ofthe brainstem.Moreover,the involve-
ment in descending inhibition oftrigeminal activity
evoked by dural stimulation has only been shown for
the ventrolateral PAG5,39,and analgesia induced by cen-
tral stimulation was obtained in humans only from the
thalamus and PAG35.
In summary,in our view,the available experimental
evidence points to CSD as the key event for episodic
activation ofthe TGVS,resulting in migraine headache.
Dysfunction ofbrainstem nuclei that are involved in the
central control ofpain might exert a permissive role by
favouring central trigeminal hyperexcitability (FIG.3).
If we accept the importance of CSD, then the
central question becomes:what makes the cortex of
migraineurs susceptible to CSD?
Altered cortical excitability in migraineurs.As transient
synchronized neuronal excitation precedes CSD21,
changes in cortical excitability must underlie the
migraine attack. Independent evidence for altered
neuronal excitability in migraineurs emerges from
TRANSCRANIAL MAGNETIC STIMULATION(TMS),recordings of
cortical potentials and psychophysics.
MO and MA patients show more visual discomfort
and illusions than control subjects when shown appro-
priate visual stimuli, and such stimuli can induce
migraine attacks.These abnormalities probably involve
visual cortex dysfunction compatible with hyperexcita-
bility, especially in MA patients40. When applying
TMS to the visual cortex,most41–43,but not all44authors
have found either a decreased threshold to produce
PHOSPHENES or a higher fraction of people reporting
phosphenes in MA and MO.This INTERICTALvisual cortex
hyperexcitability is probably due to reduced intracortical
A technique that is used to
induce a transient interruption
ofnormal activity in a relatively
restricted area ofthe brain.It is
based on the generation ofa
strong magnetic field near the
changed rapidly enough,will
induce an electric field that is
sufficient to stimulate neurons.
Luminous perceptions that are
elicited by excitation ofthe
retina by means other than light
itself,as when the eyeballs are
pressed through closed lids.
Refers to events that occur
between attacks or paroxysms.
Electrical potentials that are
generated in the brain as a
synchronized activation of
neuronal networks by external
stimuli.These evoked potentials
are recorded at the scalp and
consist ofprecisely timed
sequences ofwaves or
A small electroencephalographic
potential that is often recorded
as subjects perform expectation-
or attention-dependent tasks.It
is also known as the expectation
or E wave.
A positive waveform in the
occurs about 300 ms after the
onset ofa stimulus,and is
related to the attentional and
working memory demands ofa
Activation, sensitization of TGVS Headache
Figure 3 |Proposed pathophysiological mechanisms in
the generation of migraine headache. Current evidence
indicates that cortical spreading depression (CSD) is the most
probable primary event in trigeminovascular system (TGVS)
activation in migraine with aura and, perhaps, also migraine
without aura. Dysfunctional brainstem nuclei involved in the
central control of pain might exert a permissive role by
favouring central trigeminal hyperexcitability. Abnormal cortical
activity might lead to CSD when enhanced activation coincides
with other triggering factors. The relationship between
abnormal cortical activity and abnormal brainstem function
remains hypothetical and unclear.
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Neurogenic inflammation.In animal models,the highly
effective triptan antimigraine drugs (5-HT1B/1D/1Frecep-
tor agonists) inhibit release ofvasoactive neuropeptides
from trigeminovascular nerve endings,and both neuro-
genic plasma extravasation and vasodilation in the
meninges.They also inhibit transmission ofnociceptive
impulses to second-order neurons ofthe trigeminocer-
vical complex69.So,their pharmacology is oflimited use
in trying to discriminate between the different pain
mechanisms.On the other hand,effective inhibitors of
plasma extravasation in animal models (such as neuro-
kinin-1 (NK-1),endothelin ET-A/B receptor antago-
nists or conformationally restricted triptan analogues)
with no effect on transmission in the trigeminocervical
complex lack clinical efficacy in the treatment of
migraine69.Substance P was not found to be increased in
the cranial venous circulation during migraine attacks6,
and it is not even clear whether plasma extravasation
occurs in humans during migraine70.
CGRP, the main neuropeptide that is released by
activated trigeminovascular afferents during migraine6,7,
is a potent vasodilator.Neurogenic vasodilation pro-
duced by CGRP might further stimulate the nociceptive
afferents and contribute to pain.In rats,vasodilation of
the middle meningeal artery produced by CGRP infu-
sion does not activate the second order neurons in the
TNC,but does cause the sensitization and the facilita-
tion ofnon-nociceptive central sensory transmission
that is mediated by these cells71.CGRP infused intra-
venously in migraineurs dilates the middle cerebral
artery (MCA) and generates a delayed headache with
most of the characteristics of migraine72. However,
sildenafil induces migraine without dilation of the
MCA11,and there is no clear evidence for significant
dilation ofthe MCA during migraine attacks10.Unlike
the 5-HT1B/1D/1Fagonists,the 5-HT1Fselective agonist
LY334370 lacks vasoconstrictive effects and does not
inhibit CGRP-mediated neurogenic dural vasodilation
in guinea pigs73,but shows clinical efficacy in phase 2
clinical trials74.The ability ofLY334370 to inhibit TNC
neurons that respond to dural stimulation75indicates
that inhibition ofnociceptive transmission to second
order neurons might be the key mechanism for the
antimigraine effect oftriptans.
In summary,the current evidence indicates that,if
present in humans,neurogenic inflammation might not
be sufficient to produce pain in migraine.
Sensitization. It has been indicated that the typical
throbbing pain of migraine, and its worsening after
coughing or other normally innocuous activities that
increase intracranial pressure,might be due to increased
responsiveness (sensitization) of trigeminovascular
afferents to mechanical stimuli.Indeed,chemical stimuli
such as K+,protons or inflammatory agents applied to
the rat dura activate the trigeminovascular afferents and
sensitize them to mechanical stimuli22.Interestingly,
CSD leads to an increased extracellular concentration of
many ofthese sensitizing substances66.
Evidence for sensitization ofsecond-order trigeminal
neurons during migraine attacks comes from recordings
hypothesis is the normalization of habituation in
migraineurs by high-frequency repetitive TMS stimula-
tion, which is known to excite the cortex and could
normalize preactivation levels59.Sensory cortices are
under the control ofnoradrenergic,cholinergic and sero-
tonergic (5-hydroxytryptamine- or 5-HT-mediated)
inputs60.Noradrenergic (from the locus coeruleus) and
cholinergic (from the nucleus basalis) inputs enhance
arousal and attention,and lead to EEG activation in the
neocortex.5-HT-containing projections from the dorsal
raphe can decrease cortical excitability61.This raises the
important question of whether migraine-associated
abnormalities in evoked potentials and cortical excita-
bility are related to altered control by subcortical
Alterations of5-HT,noradrenaline,adrenaline and
dopamine levels in plasma or cerebrospinal fluid,and
of sympathetic function parameters in migraineurs
have been reported,but the data are often conflicting
and their pathophysiological relevance remains unclear.
A more consistent finding is a reduction of platelet
5-HT during attacks in MO patients56,62.However,no
correlation was found between platelet or plasma 5-HT
contentand the interictally abnormal habituation of
P300 latency,which became normal in the attack56.
The literature on cortical excitability in migraineurs
is controversial,prone to several interpretations,and
muddied by both methodological problems and con-
founding variables ofthe disease itself(such as age,dis-
ease duration,attack frequency and neurophysiological
periodicity).However,most ofthe consistent findings
point to hyperexcitability and enhanced responsiveness
ofthe cerebral cortex to external stimuli in both MA
and MO patients.The cyclic changes in cortical activity
might render the cortex vulnerable to attacks and lead to
initiation ofCSD when enhanced activation coincides
with other triggering factors (FIG.3).
The mechanisms that underlie the cortical hyperex-
citability and its periodicity remain unknown and might
be multifactorial.Excessive excitation due to abnormal
release ofexcitatory neurotransmitters is a possibility that
is supported by the higher plasma concentration ofgluta-
mate in migraineurs63and by the alterations in Ca2+chan-
nel function produced by FHM mutations (see later).
Alternatively,hyperexcitability might be due to reduced
intracortical inhibition.Although controversial64,65,low
brain Mg2+and altered brain energy metabolism would
also favour CSD.It remains unclear to what extent and
how monoaminergic projections from brainstem nuclei
contribute to the altered cortical excitability.The extent to
which some ofthe cortical and/or subcortical alterations
are affected by repetitive CSD is also not clear,as CSD
produces long-lasting changes in gene expression66
and might affect subcortical structures67.Moreover,a
reduction of PAIRED-PULSE DEPRESSIONin cortical slices after
repetitive CSD has been reported68.
Two main pain mechanisms have been considered:neu-
rogenic inflammation ofthe meninges,and peripheral
and central trigeminal sensitization.
When two depolarizing stimuli
are delivered in close succession
to a group ofaxons,their average
response to the second one is
sometimes smaller than to the
first.This form ofshort-term
plasticity is more common at
inhibitory than at excitatory
3 9 2 |MAY 2003 |VOLUME 4
R E V I E W S
nearly always present in FHM attacks,usually in the
order:visual,sensory,motor and aphasic symptoms,
and they last longer than in MA89.By contrast to other
types ofmigraine,some FHM patients can have atypical
severe attacks with impairment of consciousness
(coma) and/or prolonged hemiplegia that lasts several
days.Moreover,about 20% ofFHM families show per-
manent cerebellar symptoms ofprogressive cerebellar
FHM is genetically heterogeneous. Mutations in
CACNA1A (chromosome 19p13),the gene coding for
the pore-forming α1-subunit ofCaV2.1 — the voltage-
gated P/Q-type Ca2+channel — are associated with the
so-called type 1 FHM (FHM1),and are found in about
50% offamilies tested,comprising all the families with
cerebellar symptoms and most ofthose with coma91–93.
Recently, MISSENSE MUTATIONSin ATP1A2(chromosome
1q23),the gene encoding the α2-subunit ofthe Na+/K+
ATPase,were found in two FHM families94,defining the
so-called type 2 FHM (FHM2).The role ofCACNA1A
in common forms ofmigraine is under debate.LINKAGE
and SIB-PAIRS ANALYSESare consistent with the involvement
of the CACNA1A-encompassing region of chromo-
some 19,especially in MA95,96,but a gene other than
CACNA1A isprobably involved1,97.
CaV2.1 channels: localization and function.CaV2.1 chan-
nel expression is almost exclusively restricted to neuronal
and neuroendocrine (such as pituitary and pancreatic β)
cells.CaV2.1 channels are located in presynaptic terminals
and somatodendritic membranes throughout the brain98,
and have a prominent role in controlling neurotransmit-
ter release.In many central synapses,they are preferen-
tially located at the release sites and are more effectively
coupled to neurotransmitter release than are other Ca2+
channel types99–101.Binding ofCaV2.1 channels to SNARE
PROTEINScontributes to this preferential localization100.The
somatodendritic localization ofCaV2.1 channels points to
additional postsynaptic roles in, for example, neural
excitability102–104 and gene expression105.
The expression of CaV2.1 channels is particularly
high in the mammalian cerebellum98,106, where P/Q
channels account for most of the Ca2+current in
Purkinje cells and a large fraction ofthe current in gran-
ule cells107–109,and where they have a predominant role
in both excitatory and inhibitory neurotransmis-
sion99,110–112.Moreover,in the cerebellum,this type of
channel is postsynaptically involved in spike generation,
signal processing,neural excitability,plasticity and sur-
vival104,113,114.Mice with a null mutation in the Cacna1a
gene show severe cerebellar ataxia and DYSTONIA,together
with selective progressive cerebellar degeneration114,115.
Different mouse strains with spontaneous CaV2.1α1
mutations suffer from ataxia and show reduced P/Q-
type currents in Purkinje cells (see REF.93 for review).
About halfofthe CaV2.1α1 mutations that are linked to
FHM also cause progressive cerebellar symptoms.In
humans,other neurological disorders with cerebellar
dysfunction,such as episodic ataxia type 2 and spino-
cerebellar ataxia type 6 (REFS 91,116), are caused by
ofnociception-specific blink reflex responses76,and from
the presence in most migraine patients of cutaneous
ALLODYNIAwithin and outside the referred pain area in the
periorbital region77.Periorbital allodynia was interpreted
as a reflection ofthe sensitization oftrigeminal dorsal
horn neurons receiving convergent input from the
meninges and the periorbital skin;allodynia outside the
referred pain area was interpreted asa reflection ofsensi-
tization of third-order thalamic trigeminal neurons.
After chemical stimulation ofthe rat dura,TNC neurons
receiving convergent input from dura and skin showed
long-lasting (up to 10 h) increases in cutaneous
mechano- and thermosensitivity,and sensitivity to dura
indentation78.The gradual spatial and temporal spread
ofallodynia and its expression are consistent with the
idea that initiation ofcentral sensitization depends on
the incoming impulses from trigeminovascular nocicep-
tors79. Instead, maintenance of central sensitization
seems to be independent ofthe afferent input from sen-
sitized nociceptors,as indicated by the fact that anaes-
thetic block ofthe primary dural afferent after chemical
stimulation ofthe dura did not inhibit the long-lasting
cutaneous hypersensitivity in rats78.
Activity-dependent plasticity in dorsal horn
neurons80and/or alterations ofendogenous central pain
modulatory pathways,including the PAG5,are plausible
hypothetical mechanisms for the maintenance ofcen-
tral sensitization.Trigeminal hyperexcitability might
persist between migraine attacks,as indicated by mea-
surements ofnociceptive corneal reflex81and trigeminal
event-related potentials elicited by selective stimulation
An important role for nitric oxide in migraine has
been indicated by the finding that intravenous infu-
sions ofglyceryl trinitrate (an exogenous nitric oxide
donor) produced a delayed headache in migraineurs
that was indistinguishable from a spontaneous migraine
attack.Moreover,nitric oxide synthase (NOS) inhibitors
improve headache pain scores in spontaneous attacks
of migraine83. Animal experiments with either an
exogenous nitric oxide donor or NOS inhibitors pro-
vide evidence for a role of nitric oxide in mediating
activation and/or sensitization ofthe TGVS after dural
stimulation23,84,85,and in mediating central sensitiza-
tion of TNC neurons receiving dural input86–88.The
specificity of the effect of systemically applied nitric
oxide donors on TNC neurons that receive dural input
indicates a possible indirect effect through nitric oxide
stimulation ofTGVS that leads to prolonged activation
of the neuronal NOS in TNC and initiates central
Familial hemiplegic migraine
The main symptoms ofheadache and aura (as well as
the accompanying symptoms ofnausea,photophobia
and phonophobia) ofFHM attacks are very similar to
those ofMA,and both types ofattack might alternate in
patients and co-occur within families.FHM is charac-
terized by obligatory motor aura symptoms that consist
ofmotor weakness or paralysis,which is often,but not
always,unilateral.Three or four aura symptoms are
The perception ofa stimulus as
painful when previously the
same stimulus was reported to
Lack ofmovement coordination
that is commonly associated
with cerebellar damage.
An involuntary,rapid and
rhythmic movement ofthe
Mutations that result in the
substitution ofan amino acid in
An analysis ofthe frequency of
co-inheritance ofa pair of
genetic markers to obtain an
index oftheir physical proximity
on a chromosome.
A means to establish whether
affected siblings have the same
allele at a particular locus.
A family ofmembrane-tethered
coiled-coil proteins that are
required for membrane fusion
in exocytosis (such as during
neurotransmitter release) and
other membrane transport
complexes are formed between
vesicle SNAREs and target-
membrane SNAREs,they pull
the two membranes close
them to fuse.
The occurrence ofdyskinetic
movements due to alterations of
NATURE REVIEWS |NEUROSCIENCE
VOLUME 4 |MAY 2003 |3 9 3
R E V I E W S
In the dorsal horn ofthe spinal cord,CaV2.1 channels
are primarily located in nerve terminals,but show little,
ifany,co-localization with substance P (REF.136).In ani-
mal models of persistent pain, selective blockade of
spinal P/Q channels has disclosed a role for these chan-
nels in the initiation (but not the maintenance) ofcentral
sensitization, possibly through their control of
glutamate release from excitatory interneurons137.P/Q
channels account for 50% ofthe Ca2+current in dissoci-
ated spinal interneurons107,and have an important role
in controlling release from inhibitory spinal interneu-
rons137,138.Leanermice show enhanced acute thermal
nociceptive responses,proposed to be due to impaired
presynaptic inhibition by GABA interneurons but
reduced acute mechanical nociceptive responses139.
Functional consequences ofFHM mutations.At least
fourteen different missense mutations in CACNA1A
have been reported to be associated with FHM1 (30
families,4 sporadic cases).All ofthese mutations result
in substitutions ofconserved amino acids in important
functional regions ofthe channel,including the pore-
lining segments and the voltage sensors (FIG.4a)92,93.
Symptom variability between subjects with the same
mutation indicate that other genetic or environmental
factors also influence the phenotype.Pure FHM1,and
FHM1 with cerebellar symptoms (FHM1+PCA),are
associated with distinct mutations90.A strong correla-
tion between the frequent T666M mutation and the
FHM1+PCA phenotype was found. T666M also
showed the highest PENETRANCE of FHM (98%) and of
incidence of severe attacks with coma (50%)90. The
S218L mutation was found in patients from two families
with severe cerebral oedema and coma triggered by
minor head trauma140. Other variable neurological
symptoms were present,including typical FHM attacks
and progressive ataxia, which perhaps place these
patients at the far end ofthe migraine spectrum92.
The functional consequences ofFHM1 mutations on
recombinant CaV2.1 channels have been investigated in
heterologous expression systems141–144 and,more recently,
in neurons from Cacna1a–/– mice expressing human
CaV2.1α1subunits144.The seven FHM1 mutations that
have been analysed (FIG.4a) alter both the single-channel
biophysical properties and the density of functional
channels in the membrane.A common functional effect
ofFHM1 mutations is to shift the activation curve of
CaV2.1 channels to more hyperpolarized voltages,there-
fore increasing their open probability,over a broad volt-
age range.The increase in open probability is more than
enough to compensate for the reduction in unitary
current and conductance that is produced by some
mutations.So,a common functional effect ofthe FHM1
mutations is to increase Ca2+influx through single
human CaV2.1 channels over a large voltage range144.
Moreover, Ca2+influx through mutant channels can
occur in response to small depolarizations that are insuf-
ficient to open wild-type channels.The FHM1 muta-
tions also affect the kinetics ofinactivation ofCaV2.1
channels, but the effects are variable and result in
increased,decreased or unaffected inactivation during a
CaV2.1 channels are expressed in all structures that
are known to have an important role in the pathogenesis
ofmigraine and/or the expression ofthe migraine pain.
In the cerebral cortex,Cav2.1 channels are located in the
soma, dendrites and synaptic terminals of most
neurons98,117.They account for about one third ofthe
Ca2+current in dissociated cortical neurons107,118and for
the largest fraction ofthe action potential-evoked Ca2+
influx in single boutons oflayer 2–3 pyramidal cells,
where they also mediate almost 40% of the action
potential-evoked Ca2+influx in dendritic spines and
shafts119.P/Q channels contribute to the regulation of
the firing behaviour (in particular SPIKE-FREQUENCY ADAPTA-
TION) ofcortical neurons through activation ofCa2+-
activated K+channels and the generation ofafterhyper-
polarization103. Release of glutamate from cortical
neurons depends predominantly on P/Q-type chan-
nels101,120,whereas the release ofGABA (γ-aminobutyric
acid) depends mostly on the N-type,with a secondary
role for the P/Q-type at some synapses117.In LEANERMICE,
with a Cav2.1 mutation that reduces the channel open
probability and that shifts its activation curve to more
depolarized voltages121,122,a strong decrease in glutamate
and almost no change in GABA release was measured in
the neocortex by in vivomicrodialysis123.Interestingly,
this mouse also showed a striking elevation in the
threshold for initiating CSD,and a slower velocity and
frequent failure ofpropagation ofCSD123.These data
show the importance ofP/Q channels in the initiation
and spread of CSD,and support the conclusion that
reduced Ca2+entrythrough Cav2.1 channels reduces
neuronal cortical network excitability and makes the
cortex more resistant to CSD (see also REF 124).
There is evidence for the localization ofCaV2.1 chan-
nels in brainstem nuclei that are involved in the central
control ofnociception,including the PAG,dorsal raphe
and raphe magnus125,126.P/Q-type channels account for
30–40% ofthe Ca2+current in PAG127,128,dorsal raphe129,
caudal raphae102, locus coeruleus130and substantia
nigra131,and contribute to the generation ofAHP and to
the regulation offiring in caudal raphe neurons102.In
the rat model ofTGVS activation,blockade ofP/Q-type
channels in the ventrolateral PAG facilitates trigeminal
nociception (as inferred from the firing rate ofnocicep-
tive TNC neurons that receive inhibitory projections
from PAG),pointing to a role of CaV2.1 channels in
the descending inhibitory system that regulates the
P/Q-type channels account for a large proportion
(40%) ofthe Ca2+current ofdissociated trigeminal gang-
lion neurons133and,together with N-type channels,they
control CGRP release from capsaicin-sensitive trigemino-
vascular afferents134.The sequiterpene α-eudesmol — a
slightly selective P/Q-type blocker — inhibits neurogenic
vasodilation in facial skin and plasma extravasation in the
dura after electrical stimulation of the trigeminal
ganglion in vivo135.It remains unknown whether P/Q
channels are involved in neurotransmitter release from
trigeminovascular afferent terminals in the TNC,but
there is evidence for localization ofCaV2.1 channels in a
small number ofcells in the spinal trigeminal nucleus126.
A decrease in the rate ofaction
potentials fired by a neuron
under prolonged depolarization.
Mice with mutations in
Cacna1a.They are characterized
by marked cerebellar atrophy
that is accompanied by ataxia,
wobbly gait and dyskinesia.
The probability that an
individual with a particular
genotype will manifest a given
penetrance corresponds to the
situation in which every
individual with the same specific
genotype manifests the
phenotype in question.
A portion ofthe presynaptic
membrane that faces the
postsynaptic density across the
synaptic cleft.It constitutes the
site ofsynaptic vesicle clustering,
docking and transmitter release.
3 9 4 |MAY 2003 |VOLUME 4
R E V I E W S
(REFS 142,144and D.P.,unpublished observations).As a
consequence,the whole-cell Ca2+current density was
either increased or decreased,depending on the muta-
tion.In neurons,the four FHM1 mutations analysed,
including R192Q,decreased the density offunctional
channels in the membrane,together with the maximal
CaV2.1 current density.CaV2.1 current densities were
similar to wild type at lower voltages because of the
negatively shifted activation ofthe FHM1 mutants144.
Given the two apparently contradictory functional
effects that are common to all FHM1 mutations
analysed so far (gain offunction at the single-channel
level for voltages lower than –10 mV;loss offunction at
the whole-cell level for voltages higher than –20 mV,
with ‘function’defined as the amount ofCa2+influx in a
certain time period),the FHM1 phenotype at the synap-
tic ACTIVE ZONES might be different from that at the
soma144.Phasic neurotransmitter release at each release
site is controlled by a cluster ofonly a few Ca2+channels
that are located sufficiently close to the Ca2+sensor to
contribute to the local Ca2+increase that triggers release
in response to single action potentials145.Given the pref-
erential localization ofCaV2.1 channels at the release sites
in many central excitatory synapses,and their specific
interaction with presynaptic proteins,a reasonable pre-
diction is that the number ofspecialized Ca2+channels at
each release site will remain similar in wild-type and
mutant synapses,despite a reduced number ofmutant
channels in the soma.The FHM1 synaptic phenotype
would then be mainly determined by the mutational
changes in single-channel Ca2+influx,and therefore
be a gain-of-function phenotype, characterized by
increased action potential-evoked Ca2+influx at the
active zones146and increased neurotransmitter release
in synapses where the Ca2+sensor is not saturated (FIG.
4b).FHM1 mutations (with an opposite synaptic phe-
notype to the leanermutation) are then expected to
increase the release ofglutamate in the cortex (leaving
that ofGABA relatively unchanged),increase neuronal
cortical network excitability and make the cortex more
susceptibile to CSD.
The gain-of-function synaptic FHM1 phenotype
predicts hyperexcitability ofnociceptive trigeminovas-
cular pathways,due to enhanced release ofvasoactive
neuropeptides from perivascular nerve endings and,
possibly,facilitation ofsensitization ofsecond-order
central trigeminal neurons.It is not clear whether the
PAG CaV2.1 channels that are involved in pain inhibi-
tion are postsynaptic or presynaptic.Furthermore,the
projection ofPAG neurons to raphe neurons can cause
either excitation or inhibition ofTNC second-order
neurons.It is therefore difficult to predict the conse-
quences ofmutant FHM1 channels on central control
of trigeminal nociception. KNOCK-IN mouse models
containing human FHM1 mutations will be instrumen-
tal in elucidating how alterations of CaV2.1 channel
function cause FHM and its typical episodic symptoms.
Both FHM2 missense mutations recently found in
ATP1A2cause loss offunction ofthe Na+/K+ATPase94.
Impaired clearance ofK+ by astrocytes,where expression
ofthe α2- ATPase isoform is particularly high147,might
train ofpulses,depending on the mutation141–143.Whereas
FHM1 mutant channels expressed in neurons or HEK293
cells showed similar alterations in single-channel func-
tion,the changes in the density offunctional channels in
the membrane were different in the two cell types144.
In HEK293 cells,the density offunctional channels in
the membrane was reduced by most mutations, but
was increased by two of them — R192Q and D715E
The insertion ofa mutant gene
at the exact site in the genome
where the corresponding wild-
type gene is located.This
approach is used to ensure that
the effect ofthe mutant gene is
not affected by the activity ofthe
1 2 3 4 561 2 3 4 561 2 3 4 561 2 3 4 56
FHM1 + PCA
Soma phenotype: loss of function at voltages > –20 mV
Synaptic phenotype: gain of function
Single-channel phenotype: gain of function at voltages < –10 mV
Figure 4 |Functional effects of type 1 familial hemiplegic migraine (FHM1) mutations on
neuronal Cav2.1 channels. a | Location of FHM1 (orange) and FHM1 with cerebellar symptoms
(FHM1 + PCA; purple) mutations in the secondary structure of the Cav2.1 α1-subunit. Triangles
indicate mutations, the functional consequences of which have been studied so far. b | Functional
effects of FHM1 mutations on neuronal Cav2.1 channels. All FHM1 mutations analysed so far
increase Ca2+influx through single Cav2.1 channels for voltages lower than –10 mV (single-
channel gain-of-function phenotype), and decrease the density of functional channels in the
somatic membrane and the soma Ca2+current density for voltages higher than –20 mV (soma
loss-of-function phenotype). Functional channel complexes with FHM1 mutations (orange) and
wild-type channels (blue) are shown. c | Synaptic phenotype. Cav2.1 channel clusters that are
associated with synaptic vesicles contain only a few channel complexes. Decreased expression
density of mutant channels might not result in a relevant decrease of channel complexes
specifically targeted to synaptic vesicles. The more negative activation threshold and increased
single channel Ca2+influx of mutant channels might therefore lead to increased action potential-
evoked Ca2+influx at the active zones and increased neurotransmitter release in synapses where
the Ca2+sensor is not saturated (gain-of-function synaptic phenotype). Among other phenomena,
this could explain the enhanced cortical network excitability and, perhaps, lower cortical
spreading depression threshold in migraineurs.
NATURE REVIEWS |NEUROSCIENCE
VOLUME 4 |MAY 2003 |3 9 5
R E V I E W S
on post-operative pain in humans and that reduce cap-
saicin-induced skin hyperalgesia151,152.A phase 2 clinical
trial in acute migraine indicates that its clinical efficacy
might be comparable to that ofsumatriptan153.
Another useful therapeutic strategy would be to
reduce excitability and/or sensitization of primary
trigeminal afferents.This might be an important mech-
anism of action of sumatriptan and other triptans if
they increase a Ca2+-activated K+current and hyperpo-
larize the trigeminal ganglion cells,as proposed by some
authors154,155.The clinical efficacy ofNOS inhibitors was
mentioned earlier.Another idea currently pursued is the
desensitization ofvanilloid VR1 receptors with continu-
ous application ofVR1 agonists156.Non-peptide CGRP
receptor antagonists will represent important pharma-
cological tools to show whether CGRP that is released
during migraine attacks is just an epiphenomenon that
is triggered by trigeminal activation or whether it has an
active role in the generation ofpain and sensitization.
Ifincreased neuronal hyperexcitability and CSD are
important primary events in migraine attacks,then drugs
that decrease neuronal hyperexcitability and/or prevent
CSD should have antimigraine actions,especially as pro-
phylactic agents.As long as the molecular mechanisms
responsible for neuronal hyperexcitability are unclear,
therapies will aim at the pharmacological increase of
inhibitory neurotransmission, such as with valproic
acid157,or reduction ofexcitatory neurotransmission.
Inhibition of CSD is not a property of known
antimigraine drugs,but could represent an attractive
target for new prophylactic strategies.Unfortunately,the
mechanisms of CSD initiation and propagation are
unclear,although it is known that NMDA receptors are
involved21.This can explain the efficacy of ketamine
in relieving aura in some patients with FHM158.
Interestingly,tonabersat (SB-220453),a new benzopy-
ran with anticonvulsant properties that acts on an
unidentified binding site, was found to block CSD
induced by KCl in the feline brain159.Clinical studies
with this compound should provide valuable informa-
tion about the role ofCSD as a primary mechanism,not
only in MA,but also in MO.
On the basis of the alterations in CaV2.1 channel
function in FHM1 and those found in leanermice with
increased CSD threshold,one could speculate that drugs
capable ofshifting the activation range ofCav2.1 chan-
nels to more depolarized voltages might inhibit CSD.
Concluding remarks and future directions
Most ofthe current evidence points to CSD,the phe-
nomenon that underlies the migraine aura,as the most
probable primary cause ofactivation ofthe TGVS and
consequent headache.Direct evidence that CSD can acti-
vate the TGVS has been obtained in animals.Whereas
the occurrence of CSD in MA patients has been
established, the evidence of its occurrence in MO
patients is not so strong,and further imaging data seem
to be necessary to verify the hypothesis that CSD in clini-
cally silent areas ofthe cerebral cortex causes MO.The
alternative view that migraine aura and headache are
parallel rather than sequential processes also lacks
make the cortex more susceptible to CSD.Moreover,
the specific co-localization ofthe α2-isoform with the
Na+/Ca2+exchanger in microdomains that overlie
subplasmalemmal endoplasmic reticulum indicates
that this isoform might regulate Ca2+content of this
compartment147. Its loss of function would lead to
increased local intracellular Ca2+and subplasmalemmal
endoplasmic reticulum Ca2+content94.
Implications for new therapeutic strategies
At present, acute migraine attacks are treated with
non-steroidal anti-inflammatory drugs (such as acetyl-
salicylic acid), triptans (5-HT1B/1D/1Fagonists) or
intranasal dihydroegotamine4,148.However,20–30% of
patients do not respond to these therapies and
headache recurrence is a common problem.The rec-
ommended first-line agents for migraine prevention,
including β-adrenergic receptor antagonists,valproic
acid,amitryptiline and flunarizine,are also unsatisfac-
tory in many patients4,148.So,new therapeutic strategies
On the basis ofour current understanding ofthe pain
mechanisms involved,neither inhibition ofneurogenic
vasodilation nor inhibition ofplasma protein extravasa-
tion seem to be the most effective therapeutic strategies.
Inhibition oftrigeminal nociceptive transmission to sec-
ond-order neurons,associated sensitization mechanisms
and CSD remain as more attractive possibilities.
Pre- and postsynaptic structures might serve as tar-
gets for the inhibition ofTNC.The receptors that mod-
ulate release from central terminals ofafferent fibres
seem to be good presynaptic targets.GR79236 — an
adenosine A1 receptor agonist— inhibits CGRP release
and trigeminal nucleus activation after electrical stimu-
lation of the superior sagittal sinus in animals, and
has been reported to abort acute migraine attacks in
humans149.A1 receptor agonists might act as presynaptic
inhibitors ofcentral pain transmission.
Presynaptic inhibition could also be achieved by
presynaptic Ca2+channel block.Unfortunately,there are
no data about the role ofdifferent Ca2+channel types for
neurotransmitter release at central trigeminal synapses.It
is probably controlled by Cav2.2 channels,in analogy to
other segments ofthe spinal cord.Cav2.2 blockers had
strong analgesic actions in the treatment ofneuropathic
pain in humans.Systemic toxic effects ofsuch peptide
blockers (for example,ziconotide) that are known from
clinical studies150would prevent their use in migraine.
Obviously, new generations of non-peptide, orally
bioavailable CaV2.2 inhibitors with less systemic toxicity
would have to be developed for migraine therapy.
There are also postsynaptic targets for inhibiting TNC
activation.As ionotropic glutamate receptors mediate
nociceptive transmission and central sensitization in the
trigeminal system,glutamate receptor antagonists should
also have antimigraine effects.Owing to the small thera-
peutic window of NMDA (N-methyl-D-aspartate)
receptor antagonists,non-NMDA receptor antagonists
have been developed. LY293558 — a non-selective
AMPA/kainate receptor antagonist— is clinically well
tolerated at intravenous doses that have analgesic actions
3 9 6 |MAY 2003 |VOLUME 4
R E V I E W S
in CaV2.1 channel function that are produced by FHM1
mutations point to cortical hyperexcitability as the basis
for CSD vulnerability.In leanermice,loss ofCaV2.1 chan-
nel function reduces glutamate release and cortical net-
work excitability,and makes the cortex more resistant to
CSD.The opposite gain-of-function single-channel phe-
notype of FHM1 mutants should increase glutamate
release and cortical network excitability,making the cor-
tex more susceptible to CSD.The same effect should
result from loss of function of the α2-isoform of the
Na+/K+ATPase that are associated with FHM2.Knock-in
mice carrying FHM1 mutations are beginning to become
available and will allow verification ofthese predictions.
These mice will be invaluable,not only to understand
how the alterations in channel function cause FHM and
its typical episodic symptoms,but also to understand the
pathophysiology ofmigraine in general.They will allow
us to test the hypothesis that dysfunctional antinocicep-
tive brainstem nuclei are involved in the pathogenesis of
migraine headache.Current evidence supports the view
that peripheral and central sensitization has a key role in
the generation ofmigraine pain,but the cellular and mol-
ecular mechanisms ofcentral sensitization and its main-
tenance remain largely unknown.The gain-of-function
single action phenotype ofFHM1 mutants could imply
hyperexcitable trigeminal pathways,which would make
FHM1 knock-in mice a good model for studying the
neurobiology ofmigraine pain.
sufficient experimental support. It remains unclear
whether brainstem nuclei that are involved in the central
control ofnociception are dysfunctional in migraineurs.
The mechanisms for the initiation and propagation
ofexperimental CSD remain incompletely understood,
and the molecular and cellular mechanisms that lead to
CSD vulnerability in migraineurs remain unknown.
The relationship between CSD vulnerability and the
periodic alterations in cortical excitability measured
in migraineurs is also unclear. Whether the cortex
ofmigraineurs is hypo- or hyperexcitable is still a matter
of debate, although most of the consistent findings
point to hyperexcitability, and the hyperexcitability
hypothesis seems better suited to explain vulnerability
to CSD.The mechanisms that underlie the cortical hyper-
excitability and its periodicity remain unknown and
might be multifactorial.The discovery ofcausative genes
for migraine would be crucial to direct future research
trying to answer these fundamental open questions.
The identification ofthe gene for FHM1 has intro-
duced a new perspective into the area of migraine
research by characterizing migraine also as a channelopa-
thy.As most channelopathies are disorders ofcellular
excitability, this discovery stresses the importance of
alterations in neural excitability in the pathogenesis
ofmigraine.Our understanding ofthe molecular basis
ofFHM supports the idea that migraine is a multisystem
disorder ofneuronal hyperexcitability.The alterations
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Our work is funded by the Austrian Science Fund, Telethon-Italia,
the Italian Ministry of University and Research, and the European
The following terms in this article are linked online to:
ATP1A2 | CACNA1A | Cav2.2
FHM | MA | MO
Encyclopedia of Life Sciences: http://www.els.net/
headache | migraine
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