Current Vascular Pharmacology, 2003, 1, 71-84 71

Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends

Carlos M. Villalón*, David Centurión, Luis Felipe Valdivia, Peter de Vries1 and Pramod R. Saxena1

Departamento de Farmacobiología, CINVESTAV-IPN, Czda. de los Tenorios 235, Col. Granjas Coapa, Deleg. Tlalpan,
C.P. 14330, México D.F., México and 1Department of Pharmacology, Erasmus University Medical Centre Rotterdam
“EMCR”, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands

Abstract: Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is
primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin
(5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with
associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as
ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid
circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan,
rizatriptan, naratriptan), which belong to a new class of drugs, the 5-HT1B/1D/1F receptor agonists. Compared to
sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the
vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT 1B receptors)
and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D/5-ht1F
receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the
trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the
acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B
receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction,
efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator
mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis,
etc). These alternatives will hopefully lead to fewer side effects.

INTRODUCTION
Migraine is a syndrome that affects a significant fraction
of the world population, with a higher prevalence in women
(15%) than in men (6%) [1]. Migraine is characterised by an
intense and throbbing unilateral headache associated with
anorexia, nausea, vomiting, photophobia, phonophobia
and/or diarrhoea (common migraine). Sometimes the
headache may be preceded by a focal neurological
phenomenon (“aura”) followed by headache (classical
migraine); this aura consists of certain motor (weakness or
paralysis) and/or focal neurological (scintillanting scotoma)
symptoms.
HISTORY OF HEADACHE TREATMENT
A variety of methods have been used throughout the ages
in an attempt to abort this pain; these may have been the
most appropriate at that time, and were probably seen as
“cutting edge”. Today they seem at best amusing, and at
worst cruel and barbaric.
The earliest concepts in migraine were those of the
supernatural, with migraine believed to be due to malevolent
*Address correspondence to this author at the Departamento de
Farmacobiología, CINVESTAV-IPN, Czda. de los Tenorios 235, Col.
Granjas Coapa, Deleg. Tlalpan, C.P. 14330, México D.F., México; Tel:
(Int)-(52 55)-54832854; Fax: (Int)-(52 55)-54832863; E-mail:
carlos_villalon@infosel.net.mx
beings within the head; treatment based on this idea included
incantations and application to the head of substances
intended to drive out the demons and spirits [2]. The people
living in the Neolithic period (8500-7000 BC) used the
method of trepanation, which involved removing circular
chunks of skull so that the spirits causing the headache could
escape. Although the scientific rationale behind trepanation
is not understood, it is surprising that this procedure was
performed as a treatment for migraine as late as the mid 17th
century [2,3].
The oldest known medical manuscript, the Ebers Papyrus
(dating back to about 1200 BC and discovered in the
necropolis of Thebes), contains an ancient Egyptian
prescription for migraine based on earlier medical documents
including an Egyptian papyrus of 2500 BC, as shown in Fig.
(1). Believing the gods could cure their ailments, a clay
effigy of a sacred crocodile with herbs stuffed into its mouth
was firmly bound to the head of the patient by a linen strip
[3]. Admittedly, this process may have relieved the headache
by collapsing distended vessels which were causing the pain.
Around 400 BC Hippocrates released migraine from the
realms of the supernatural by attributing it to vapours rising
from the stomach to the head and he described, for the first
time, the visual symptoms (“aura”) of migraine [2,3]. Many
years later, in the 2 nd century (AD) Galen wrote of “a painful
disorder affecting approximately one-half of the head” [4].
His term for this, “hemicrania”, was gradually transmuted
into “migraine”. Galen, like Hippocrates, believed that this
headache was caused by vapours rising from the stomach to

1570-1611/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd.

72 Current Vascular Pharmacology, 2003, Vol. 1, No. 1
Fig. (1). Ancient methods attempting to alleviate or cure headache:
Egyptian papyrus (2500 BC) which describes bandaging a clay
crocodile (with herbs stuffed into its mouth) to the head of the
sufferer and praying.
the head [4]. The hippocratic/galenic concept of migraine
survived into the 17th century, when Thomas Willis
published in 1664 his hypothesis that “megrim” was due to
dilatation of blood vessels within the head (the first
enunciation of a vascular theory) [2,3]. This theory was
strengthened by the fact that migraine intensity was
decreased by a compression of the superficial temporal
artery. In the 19th century, however, the vascular origin of
migraine was undermined by a conflicting theory that the
prime event was a neurological dysfunction. Thus, in 1873,
Edward Liveing proposed that migraine was due to “nerve
storms evolved out of the optic thalamus” [2]. However, like
the vascular theory, there was nothing but conjecture to
support this neurogenic theory [2,3]. Towards the end of the
19th century attempts were made to reconcile both theories.
Thus, Moebius stated in 1898 that “parenchyma is the
master, circulation the servant”, and that both brain and
blood vessels dysfunctions were necessary to produce an
attack of migraine [2]. Almost simultaneously, ergot (the
product of the fungus Claviceps purpurea that grows upon
rye) was introduced in 1884 by W.H. Thomson as an
effective remedy for migraine [5]; physicians, however, were
aware of the intoxication risk when taken frequently
(ergotism or St. Antony’s Fire), with descriptions dating
back to the Middle Ages [6]. Ergotism is characterized by
gangrene of the feet, legs, hands and arms due to a potent
and long-lasting vasoconstriction. Thus, the introduction of
ergot and the subsequent isolation of the first pure ergot
alkaloid, ergotamine, by Stoll in 1920 [7] represent a
remarkable accomplishment as the beginning of an effective
therapy for the treatment of migraine.
THEORIES OF MIGRAINE IN THE EARLY 20TH
CENTURY
The antimigraine efficacy of ergotamine was established
in the 20th century, with the advantage over ergot that the
occurrence of ergotism was less frequent [8]. However, due
to the lack of any scientific studies there was still a
Villalón et al.
controversy between the opposing vascular and neurogenic
theories of migraine. Fortunately, Harold Wolff was the first
researcher to place migraine on a scientific basis [9-11].
During a significant number of migraine attacks, pulsations
in the temporal branches of the external carotid artery were
demonstrated using an external tambour and pain could be
relieved either by physical compression or by ergotamine
[9]. These and other findings [10,11] seemed to establish the
vascular theory of migraine beyond any doubt. Nevertheless,
in 1983, the vascular theory apparently weakened when [12]
demonstrated that blood flow changes similar to those
known to occur in migraine could be produced by electrical
stimulation of brainstem structures. This finding revived the
neurogenic theory, stimulating studies which investigated the
relationship between the trigeminal nerve and the cranial
vasculature. Thus, in 1984, Moskowitz [13] showed that
trigeminovascular axons from blood vessels of the pia mater
and dura mater release vasoactive peptides producing a
sterile inflammatory reaction with pain. During this
neurogenic inflammation, the trigeminal ganglion is
stimulated and this induces neurogenic protein extravasation;
then some vasodilator peptides are released, including
calcitonin gene-related peptide (CGRP), substance P and
neurokinin A. In fact, some studies have demonstrated that
antimigraine drugs like ergotamine can block neurogenic
plasma extravasation in rat dura mater [14,15]. However,
very recent lines of evidence (discussed below) have shown
that drugs which exclusively block neurogenic plasma
extravasation in rats (without producing vasoconstriction) do
NOT have antimigraine action in humans [16,17].
VASCULAR OR NEUROGENIC THEORY ?
Admittedly, there is no definitive evidence thus far to
categorically exclude the vascular or the neurogenic theories
of migraine in view that all acute antimigraine drugs
invariably produce both cranial (carotid) vasoconstriction
(shown in animals and humans) and inhibition of the
trigemino-vascular system (centrally and/or peripherally;
shown only in rats and guinea-pigs) [18,19]. It is likely that
new tools for the investigation of migraine will resolve this
conceptual stalemate and allow a unified theory of migraine
to evolve. For convenience, the present review will consider
the pathophysiology and therapeutics of migraine on the
basis of a neurovascular hypothesis.
MIGRAINE PATHOPHYSIOLOGY
Based on the clinical features of migraine, three distinct
phases can be discerned: an initiating trigger, an aura and,
finally, the headache. Although limited information is
available about the trigger phase, there is indeed now a better
understanding of the pathophysiology of migraine [20,21].
Some results indicate that the initiating trigger, involving the
brainstem as ‘migraine generator’ [22], may be linked to a
‘familial’ channelopathy [23,21]. The subsequent events
leading to the symptoms observed during the aura and
headache phases can be explained on the basis of a
neurovascular hypothesis [24,25,21]. Thus, as illustrated in
Fig. (2), once the "migraine generator" has been switched on,
Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends Current Vascular Pharmacology, 2003, Vol. 1, No. 1 73

Fig. (2). Diagram showing putative changes in migraine and the therapeutic targets of acutely acting antimigraine drugs. These drugs are
believed to owe their antimigraine efficacy to direct vasoconstriction of dilated cranial blood vessels (1), inhibition of trigeminally-induced
cranial vasodilatation (2), plasma protein extravasation (3) and/or central neuronal activity (4). Only lipophilic, brain penetrant triptans (not
sumatriptan) exert central trigeminal inhibitory effects. For details see text. Modified from [18] 1999a Eur.J.Pharmacol. 375: 61-74. TNC,
trigeminal nucleus caudalis.

regional cerebral blood flow decreases, possibly following a
wave of cortical spreading depression [26]. In patients where
cerebral blood flow falls below a critical value, the
corresponding aura symptoms may appear. The reduced
cerebral blood flow is then followed by a vasodilatation
during headache, probably due to changes in the activity of
the neurones innervating cranial arteries (e.g. in the
dura mater, base of the skull and scalp). Besides
noradrenaline and acetylcholine, immunohistochemical
studies have demonstrated the presence of several
vasodilator transmitters in perivascular nerves supplying
intracranial blood vessels, including 5-HT, vasoactive
intestinal peptide (VIP), nitric oxide (NO), substance P,
neurokinin A and CGRP [27]. As discussed elsewhere [28],
NO may also be involved in migraine pathophysiology and
inhibition of its synthesis seems to be of therapeutic
relevance [29]. In any case, cranial vasodilatation leads to
enhanced blood volume following each cardiac stroke, with a
consequent augmentation in pulsations within the affected
blood vessels, as shown in Fig. (2). The augmented
pulsations can then be sensed by "stretch" receptors in the
vessel wall and the resultant increase in perivascular
(trigeminal) sensory nerve activity provokes headache and
other symptoms. This trigeminal stimulation may also
release neuropeptides, thus reinforcing vasodilatation and
perivascular nerve activity [for details and references, see
25]. As illustrated in Fig. (2), within the framework of the
neurovascular hypothesis of migraine, acutely acting
antimigraine drugs (e.g. ergotamine) would constrict dilated
cranial extracerebral blood vessels [30,31,24], reduce
neuropeptide release and plasma protein extravasation across
dural vessels [15,32] and inhibit impulse transmission
centrally within the trigeminovascular system [33,20].
74 Current Vascular Pharmacology, 2003, Vol. 1, No. 1
TREATMENT OF MIGRAINE
The drugs used in the treatment of migraine can be
divided into two groups: agents that abolish the acute
migraine headache (acute antimigraine drugs; e.g.
ergotamine; sumatriptan) and agents aimed at its prevention
(prophylactic drugs; e.g. methysergide) [8,34,35]. Both
groups include specific drugs and non-specific drugs, but the
present review will be exclusively focussed on the
development of acute antimigraine drugs.
Acute Antimigraine Drugs
Non-specific Drugs
These drugs are used to treat the symptoms
accompanying the headache, such as antiemetics
(metoclopramide), non-steroidal anti-inflammatory drugs
(NSAID’s; e.g. aspirin) and anxyolitics/sedatives
(chlorpromazine) [34,35]. NSAID’s are the most popular
agents because, in addition to being cheap, effective and easy
to administer, they allow the patient to control his/her own
therapy. Unfortunately, they produce headache after long-
term use [8,34,35].
Specific Drugs
These drugs can abolish the headache by producing
selective vasoconstriction of extracranial blood vessels,
including the external carotid bed. Examples include the
ergot alkaloids, ergotamine and dihydroergotamine [34,35].
Although highly effective, the use of ergotamine should be
restricted to patients having infrequent severe migraine
attacks [8] in view that it may produce: (i) prolonged
peripheral vasoconstriction symptoms which are reminders
of ergotism (numbness and tingling of the fingers and toes);
(ii) cardiac pain suggestive of angina pectoris and
palpitations as a result of coronary vasospasm; and
(iii) nausea and vomiting by a direct effect on the CNS
emetic centres (problematic side effects since these are part
of the symptomatology of a migraine headache). Evidently,
ergotamine is contraindicated in patients with peripheral
vascular disease, coronary heart disease and hypertension.
These side effects are partly explained by the capability of
ergotamine and other ergots to interact with a wide variety of
different receptors types including serotonergic (5-HT1A,
5-HT1B, 5-HT1D, 5-ht1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-ht5A/5B,
5-HT7), dopaminergic (D2-like) and adrenergic (α1 and α2)
[for references see 36].
IN SEARCH OF THE IDEAL ANTIMIGRAINE DRUG
As previously pointed out, the introduction of ergotamine
opened a new era of rational pharmacotherapy in the acute
treatment of migraine; however, its side effects,
contraindications and interactions with an array of different
receptors led to the speculation that a more selective cranial
vasoconstrictor agent would be an effective antimigraine
drug devoid of the inconveniences associated with
ergotamine. Thus, in 1972, Humphrey and colleagues
initiated a long-term project aimed at identifying novel
therapeutic agents in the treatment of migraine [37]. The
Villalón et al.
goal of this project was to develop selective vasoconstrictors
of the extracranial circulation based on the vascular theory of
migraine (see above) and the lines of evidence supporting the
role of 5-HT in its pathogenesis [8,38], namely that:
(i) during an attack of migraine, high quantities of
5-hydroxyindole acetic acid (5-HIAA) are excreted [39];
(ii) some drugs that deplete monoamines (reserpine) can
provoke a migraine attack [40]; and (iii) a slow i.v infusion
of 5-HT can abort an attack of migraine [40,41]. The factor
restricting the clinical use of 5-HT as an antimigraine agent
was the prevalence of side effects [40,41], including changes
in heart rate, vasodilatation in some vascular beds (e.g.
cutaneous blood vessels) and vasoconstriction in others (e.g.
the external carotid bed), gastrointestinal effects, etc [42,43].
The antimigraine efficacy of 5-HT, nevertheless, suggested
the existence of a specific 5-HT receptor involved in the
relief of headache; hence, it was proposed [44] that a drug
which could mimic the beneficial effects of 5-HT without its
side-effect profile would provide an effective therapy for
migraine. The aim, therefore, was to identify such a drug
which would selectively constrict the cranial blood vessels
(abnormally dilated during migraine). This aim was
strengthened by the knowledge that 5-HT appeared to be
intrinsically more active as a vasoconstrictor of cephalic
blood vessels (i.e. the external carotid bed), and that the 5-
HT receptors on such vessels are different to those on
peripheral vessels [45,46].
CLASSIFICATION OF 5-HT RECEPTORS
With the conjunction of operational (selective agonists
and antagonists and ligand binding affinities), transductional
(intracellular transduction mechanisms) and structural
(molecular structure) criteria, 5-HT receptors have been
divided into seven main families, namely: 5-HT1, 5-HT2,
5-HT3, 5-HT4, 5-ht5, 5-ht6 and 5-HT 7 receptors (see Table 1).
With the exception of 5-ht5 and 5-ht6 receptors, the other
receptors have been functionally identified [42,47-50,18]. To
distinguish recombinant receptors from native, functional
receptors in whole tissues, lower case letters are used to
identify recombinant receptors [47]. This review restricts
itself to the 5-HT1 receptor family since this is the receptor
type involved in the therapeutic efficacy of acute
antimigraine drugs [18,19]. The 5-HT1 receptor is a highly
heterogeneous family, which includes at least 5 subtypes,
namely, 5-HT 1A, 5-HT 1B, 5-HT 1D, 5-ht 1E and 5-ht 1F receptors
(see Table 1). As discussed below, the selective antimigraine
drugs (sumatriptan and second generation triptans) are
agonists at 5-HT1B/1D receptors and produce selective
vasoconstriction of the carotid vascular bed [18,19].
SUMATRIPTAN: A SEMINAL DISCOVERY
After analysing several tryptamine derivatives, one in
particular drew attention, namely 3-[2-(di-methyl-
amino)ethyl]-N-methyl-1H-indole-5-methane sulphonamide
(sumatriptan, previously known as GR43175), which was
synthesised in 1984. This compound was more selective than
5-carboxamidotryptamine for the 5-HT receptors producing
vasoconstriction in the dog saphenous vein and extracranial
blood vessels, and displayed much less activity in other
Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends Current Vascular Pharmacology, 2003, Vol. 1, No. 1 75

Table 1. Classification of 5-HT Receptorsa,b

Receptor Agonists Antagonists Transduction Localization Function

5-HT1A 8-OH-DPAT WAY 100635 (-) Adenylyl cyclase Raphe nucleus Central hypotension

5-HT1Bc,d Sumatriptan SB224289 (-) Adenylyl cyclase Cranial blood vessels Vasoconstriction

5-HT1Dd PNU109291 BRL15572 (-) Adenylyl cyclase Presynaptic neurons Autoreceptor

e
5-ht 1E 5-HT Methiothepin (-) Adenylyl cyclase Cortex Unknown
d
5-ht 1F LY344864 Methysergide (-) Adenylyl cyclase CNS (-) Trigeminal system
f
5-HT 2A DOI Ketanserin (+) Phospholipase C Smooth muscle, Contraction,
platelets aggregation

5-HT2Bf BW723C86 SB204741 (+) Phospholipase C Rat fundus, Contraction, release

endothelium of NO

5-HT2Cf Ro 60-0175 SB242084 (+) Phospholipase C Choroid plexus CSF production?

+ +
5-HT3 2-Methyl-5-HT MDL72222 Na /K channel Peripheral nerves (+) Neuronal activity

5-HT4 Renzapride, BIMU8 GR 113808 (+) Adenylyl cyclase Gastrointestinal tract, (+) Neuronal activity,
pig and human atrium tachycardia

5-ht5A/5B 5-HT, ergotamine LSD ? CNS Unknown

g
5-ht6 5-MeO-T≥5-HT Ro 04-6790 (+) Adenylyl cyclase CNS Unknown
g
5-HT7 5-CT>>5-HT SB258719 (+) Adenylyl cyclase CNS, smooth muscle, Circadian rhythm,
cat atrium relaxation,
tachycardia

a
Modified from Saxena and Villalón; [42,47-50,18]. In order to distinguish recombinant receptors from functional receptors in whole tissues, lower case letters (5 htX) are
used to identify recombinant receptors.
b
CNS, central nervous system; CSF, cerebrospinal fluid; LSD, lysergic acid diethylamide; 5-MeOT, 5-methoxytryptamine; 5-CT, 5-carboxamidotryptamine; DOI, 1-(2,5-dimethoxy-
4-iodophenyl)-2-aminopropane; NO, nitric oxide; (-), inhibits; (+), stimulates.
c
The antimigraine drug sumatriptan as well as second generation triptans are agonists at 5-HT1B/1D/1F receptors. There is no selective agonist at 5-HT1B receptors thus far.
d
GR127935 equipotently antagonizes 5-HT1B/1D receptors and displays moderate affinity for 5-ht1F receptors.
e
There are no selective agonists or antagonists thus far. Very high doses of methiothepin are required to produce effective blockade.
f
DOI is an equipotent agonist at 5-HT2A, 5-HT2B and 5-HT2C receptors.
g
Although there are no selective agonists yet, sumatriptan must be inactive at 5-HT6 and 5-HT7 receptors. Mesulergine is an antagonist showing an almost 300-fold selectivity for the
cloned 5-ht7 receptor (pKD=8.2) over the cloned 5-ht6 receptor (pKD=5.8).

vascular systems [51,44]. Moreover, many studies showed
that sumatriptan is an agonist at 5-HT1B/1D receptors [47].
This drug mediates constriction of cranial large arteries (i.e.
the external carotid bed) [52-54], is effective in aborting
migraine attacks [24], but it has coronary side-effect
potential [55].
EXPERIMENTAL MODELS PREDICTIVE
ACUTE ANTIMIGRAINE ACTION
The experimental models currently known for the
discovery and development of antimigraine drugs are based
on the vascular or neurogenic theories of migraine [18].
These basically include:
Models Based on the Involvement
Vasodilatation in Migraine
These models consider cranial vasodilatation as an
integral part of the pathophysiology of migraine and that the
ergot alkaloids and sumatriptan owe their therapeutic
efficacy primarily to the constriction of dilated vessels [24].
There are several ways to investigate the effects of
antimigraine drugs on cranial blood vessels, both in vitro and
in vivo. Two of these models are discussed here.
(i) Contraction of isolated cranial blood vessels. Several
isolated blood vessels, including human cranial arteries,
OF contract in response to acute antimigraine drugs [18,19].
This effect is more marked on cranial blood vessels where,
contrary to most peripheral arteries, the 5-HT1B rather than
5-HT2 receptor is predominant [56].
(ii) Constriction of the canine external carotid bed. Over
the years [54], this vascular model (as discussed below), has
proven its worth and has been highly predictive of
antimigraine activity in the clinical setting [18,19]. Another
of Cranial advantage it offers is that one can simultaneously study a
number of major vascular beds in order to evaluate the
craniovascular selectivity of the drugs [45,57], as was the
case in the preclinical development of sumatriptan [58]. It
must, however, be realised that this model will pick up only
76 Current Vascular Pharmacology, 2003, Vol. 1, No. 1
those putative antimigraine drugs that would be effective by
constricting dilated cranial blood vessels, whatever the
mechanism.
Models Based on the Involvement of the
Trigeminovascular System in Migraine
These models consider that the above described
vasoconstrictor action may be unnecessary for antimigraine
action and that the efficacy is due to a presynaptic action on
sensory nerve endings, inhibiting neuropeptide release and
the process and/or consequence of “neurogenic"
inflammation” [15,32]. One of these models is:
Inhibition of plasma protein extravasation after
stimulation of the trigeminal nerve in the rat and guinea pig.
In this model, sumatriptan inhibits neurogenic plasma
protein extravasation [15,32]; this effect is antagonised by
the 5-HT1B/1D receptor antagonist GR127935 (see Table 1) in
both the rat and guinea pig, implying the involvement of
5-HT1B/1D receptors [59]. Moreover, in the guinea-pig the
selective 5-HT1D receptor agonist PNU109291 (see Table 1)
potently inhibits dural plasma extravasation [60,61]. Indeed,
the selective 5-ht1F receptor agonists, LY334370 and
LY344864 (see Table 1), inhibit plasma protein extravasation
in the guinea pig and rat [62,63]. Importantly, the activity of
PNU142633 in this model does not translate into
antimigraine activity in clinical trials [17]; in contrast,
LY334370 displayed antimigraine activity at doses that may
interact with extracranial vasoconstrictor 5-HT1B receptors
[16]. Moreover, [64] has questioned the involvement of
plasma extravasation in migraine, based on the lack of retinal
permeability changes during migraine attacks.
Irrespective of the validity of each model, there is little
doubt that the models with more tradition for the
development of potential antimigraine drugs are those based
on the vascular theory of migraine (see above) [45,57]. In
fact, sumatriptan was developed on experimental models
based on this theory [44], particularly the canine external
carotid bed [58]. For this reason, the present review will be
particularly focussed on our pharmacological research on
5-HT and the canine external carotid bed.
THE CANINE EXTERNAL CAROTID BED: A
RELIABLE EXPERIMENTAL MODEL TO DEVELOP
ANTIMIGRAINE DRUGS
As previously described, all effective acute antimigraine
drugs available thus far produce selective vasoconstriction of
cephalic blood vessels (i.e. the external carotid bed including
its temporal branches and arteriovenous anastomoses)
[18,19]. Experiments are carried out in anaesthetised mongrel
dogs and catheters are placed in the inferior vena cava via a
femoral vein for the administration of antagonists and in the
aortic arch via a femoral artery, connected to a pressure
transducer for the measurement of blood pressure. The right
common carotid artery is dissected free and the corresponding
internal carotid and occipital arteries are ligated. Thereafter, an
ultrasonic flow probe (4 mm R-Series) connected to an
ultrasonic flowmeter is placed around the right common carotid
artery, and the flow through this artery is considered as the
Villalón et al.
external carotid blood flow [52-54]. Bilateral cervical
vagosympathectomy is systematically performed in order to
produce one of the main features of migraine, i.e. external
carotid vasodilatation [57]. Under these conditions, 5-HT and
ergotamine can produce selective external carotid
vasoconstriction [57]. These findings confirmed the
previously observed antimigraine action of ergotamine [9-
11] and 5-HT [41,40] (see above). Interestingly, Vidrio and
Hong reported that 5-HT produced vasodilatation in animals
with intact vagosympathetic trunks [65]. These discrepancies
were explained in terms of the vascular sympathetic tone
[66], establishing that in animals with interrupted
vagosympathetic trunks (and the resulting external carotid
vasodilatation) 5-HT produces vasoconstriction, producing
the opposite effect in dogs with intact vagosympathetic
trunks [67].
PHARMACOLOGICAL PROFILE OF THE
RECEPTORS MEDIATING EXTERNAL CAROTID
VASOCONSTRICTION IN VAGOSYMPATHEC-
TOMIZED DOGS
It had been previously shown that methysergide
(non-selective 5-HT receptor antagonist), but not mianserin
or cyproheptadine (5-HT2 receptor antagonists), blocked the
vasoconstrictor responses to 5-HT in the external carotid bed
[68,57]. Since methysergide is a non-selective antagonist,
these data suggested that a novel (methysergide-sensitive)
5-HT receptor was involved. With the advent of more
selective antagonists, it was shown that the vasoconstrictor
response to 5-HT was significantly blocked by high doses of
methiothepin (a 5-HT1-like receptor antagonist) but not by
ritanserin or tropisetron, antagonists at 5-HT2 and 5-HT3/4
receptors, respectively [52]. Interestingly, sumatriptan, a
selective “5-HT1-like” receptor agonist, mimicked the
vasoconstriction to 5-HT, and this response was also blocked
by methiothepin. These data suggested the involvement of
“5-HT1-like” receptors, but not 5-HT2 or 5-HT3 or 5-HT4
receptors [52].
In 1994, the classification schemes proposed by the
NC-IUPHAR subcommittee on 5-HT receptors [47]
considered the "5-HT1-like” receptors to be different from
5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-ht1F receptors.
Considering this, we suggested that 5-HT1A, 5-HT1B or
5-HT1D are not involved in the external carotid
vasoconstrictor responses to 5-HT since these were not
blocked by: (i) (±)pindolol, a 5-HT1A/1B receptor antagonist;
(ii) propranolol, a β-blocker with affinity for 5-HT1B
receptors; and (iii) metergoline, a ligand with the highest
affinity for “5-HT1D” receptors. However, we recognised that
metergoline was a non-competitive and non-specific
antagonist and that its affinity did not correlate with its
blocking properties at functional responses. Thus, we had to
wait for more selective 5-HT1D receptor antagonists.
With the advent of GR127935 in 1996, a selective
“5-HT1B/1D” receptor antagonist [69], we observed that the
vasoconstrictor responses to 5-HT and sumatriptan, which
were unaffected by saline, were potently and selectively
antagonised by this antagonist [53]. However, the profile of
antagonism was different. Indeed, not only was the
Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends
vasoconstrictor response to 5-HT completely abolished, but
also a dose-dependent vasodilator response was unmasked.
In the case of sumatriptan, the vasoconstrictor response was
dose-dependently antagonised without unmasking the
vasodilator effect observed with 5-HT [53]. These findings
suggested that the “5-HT1-like” receptors mediating the
vasoconstrictor responses to 5-HT and sumatriptan belong to
the 5-HT1D receptor subtype [53]. In addition, a further
analysis of the vasodilator response to 5-HT in animals
systematically pretreated with GR127935 revealed that this
effect is mediated by 5-HT7 receptors [70].
However, it had been reported that in humans the 5-HT1D
receptors had two variants, called 5-HT1Dα and 5-HT1Dβ
receptors. Sumatriptan, GR127935, metergoline and
methiothepin were not able to discriminate between 5-HT1Dα
and 5-HT1Dβ receptors. Subsequently, these receptors were
redefined respectively, as 5-HT1D and 5-HT1B since the
5-HT1Dβ receptor was considered a human homologue of the
rodent 5-HT1B receptor [71]. Thus, although the rodent 5-
HT1B receptor exhibits a pharmacological profile (sensitive
to β-blockers) which differs from that of the non-rodent
species (see Table 1), they are encoded by the same gene
(but different species). With this new nomenclature
(vasoconstrictor 5-HT1B/1D receptors), the need for more
selective compounds was evident. The advent of selective
and silent antagonists (antagonists devoid of intrinsic
activity) for 5-HT1B and 5-HT1D receptors shed further light
on this matter [72]. Thus, as shown in Fig. (3a), the external
carotid vasoconstrictor responses to 5-HT and sumatriptan
were dose-dependently and specifically antagonised by the
selective 5-HT1B receptor antagonist, SB224289, but not by
the selective 5-HT 1D receptor antagonist, BRL15572 see Fig.
(3b); [73]. These data clearly indicate that 5-HT1B, but not
5-HT1D receptors mediate the external carotid
vasoconstrictor responses to 5-HT and sumatriptan. In
addition, the 5-ht 1F receptor agonist, LY344864 was inactive
as an agonist or antagonist in this model [36], a finding that
excludes the potential role of these receptors. The
implication of these findings within the context of the
vascular theory of migraine would be that the vascular
5-HT1B receptor is one of the main targets of antimigraine
drugs. Obviously, the introduction of a selective 5-HT1B
receptor agonist for the treatment of migraine (devoid of the
ability to inhibit the trigeminovascular system) is awaited
with interest.
MECHANISM OF ACTION OF ERGOTAMINE AND
DIHYDROERGOTAMINE
Although the antimigraine properties of ergotamine and
dihydroergotamine are clearly established [7,9,6], the
mechanisms involved in their vasoconstrictor action are not
well understood. These drugs can produce external carotid
vasoconstriction and can interact with 5-HT1, 5-HT2, 5-ht5,
5-HT6 5-HT 7, α-adrenoceptors and dopamine receptors [36].
Thus, we investigated the mechanisms involved in these
vasoconstrictor effects. Interestingly, both drugs produced
dose-dependent vasoconstrictor responses in the canine
external carotid bed. As shown in Fig. (4), these responses
were partially blocked by the 5-HT1B/1D receptor antagonist,
GR127935, or by the α2-adrenoceptor antagonist,
Current Vascular Pharmacology, 2003, Vol. 1, No. 1 77
yohimbine, but not by the α1-adrenoceptor antagonist,
prazosin. Interestingly, the vasoconstrictor responses to these
drugs were abolished by the combination of GR127935 and
yohimbine, confirming that 5-HT1B/1D receptors and α2
adrenoceptors are involved [36]. It should be emphasised
that the blockade of the above antagonists was specific, since
the doses of prazosin, yohimbine and GR127935 were high
enough to block the carotid vasoconstrictor responses to
phenylephrine, clonidine and sumatriptan, respectively [36].
Although, the above findings show the involvement of
5-HT1B/1D receptors and α2-adrenoceptors on the
vasoconstrictor responses to ergotamine and
dihydroergotamine, it remains to be established whether
5-HT1B or 5-HT1D receptors as well as α2A, α2B or
α2C-adrenoceptors are involved. In addition, these ergot
alkaloids may have other properties such as inhibition of
protein plasma extravasation [74].
PHARMACOLOGY OF SUMATRIPTAN AND
SECOND-GENERATION TRIPTANS
Despite its efficacy in migraine treatment, sumatriptan
has certain limitations, including low oral bioavailability,
high headache recurrence (possibly due to a short t1/2) and
contra-indications in patients with coronary artery disease
[19,18]. Therefore, a number of pharmaceutical companies
decided to develop newer triptans having agonist activity at
5-HT1B/1D receptors. Several such compounds (zolmitriptan,
rizatriptan and naratriptan) are already on the market, while
others (eletriptan, almotriptan and frovatriptan) are in
different stages of clinical development [19,18]. These
compounds will be referred to as the second-generation
triptans, since they are tryptamine derivatives and
pharmacologically comparable to sumatriptan. Zolmitriptan,
rizatriptan, naratriptan and eletriptan seem to be at least as
effective as sumatriptan in migraine therapy [21,75] and the
outcome of elaborate clinical trials with the other triptans is
awaited with interest.
RECEPTOR BINDING PROFILE OF TRIPTANS
Sumatriptan as well as the second-generation triptans
display high affinities at 5-HT1 receptors, mainly the 5-HT1B
and 5-HT1D receptors (see Fig. [5]) [76-80]. With the
exception of rizatriptan and almotriptan and, to some extent
sumatriptan, all other compounds, particularly zolmitriptan,
have a high affinity at the 5-HT1A receptor. These
compounds also interact with the 5-ht1F receptor.
Sumatriptan, zolmitriptan, eletriptan and frovatriptan display
a µM affinity at the 5-HT7 receptor, which mediates smooth
muscle relaxation [50].
PHARMACOKINETICS OF TRIPTANS
The pharmacokinetic properties of second-generation
triptans have been studied in human volunteers and migraine
patients, as shown in Fig. (6) [81-94]. Subcutaneous
sumatriptan (6 mg) is quickly absorbed with a tmax of
approximately 10 min and an average bioavailability of 96%
[95]. After oral administration of therapeutic doses (100 mg)
of sumatriptan, however, the tmax is substantially longer
(1.5 h) and, more importantly, the bioavailability is rather
78 Current Vascular Pharmacology, 2003, Vol. 1, No. 1 Villalón et al.

Fig. (3). Effect of (a) SB224289 or (b) BRL15572 on the decreases in external carotid blood flow induced by 1 min intracarotid (i.c.)
infusions of 5-HT, sumatriptan and noradrenaline (NA) in vagosympathectomized dogs. *, P<0.05 vs control. With permission from [73]
Eur. J. Pharmacol., 362: 69-72.

low (~14%). Intranasal or rectal administration of
sumatriptan does not seem to improve these parameters
much [96]. The oral bioavailability of second-generation
triptans, especially naratriptan and almotriptan, is much
improved [see Fig. ( 6)]. The latter can be partly attributed to
the more lipophilic nature of these drugs. Interestingly, the
tmax after oral administrations of zolmitriptan, naratriptan,
almotriptan and frovatriptan is not much better than that of
sumatriptan, whereas rizatriptan and eletriptan seem to reach
their peak plasma levels quicker compared to sumatriptan.
With the exception of rizatriptan, triptans are degraded
slower than sumatriptan. Especially frovatriptan has a
plasma half-life of 26-30 h [see Fig. (6)]) and, in view of the
putative relation of this parameter with headache recurrence,
the results of clinical trials with frovatriptan are awaited with
Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends Current Vascular Pharmacology, 2003, Vol. 1, No. 1 79

Fig. (4). Percent changes from baseline values of external carotid blood flow induced by 1 min intracarotid (i.c.) infusions of (a) ergotamine
or (b) dihydroergotamine in animals pretreated with either saline, GR127935, prazosin, yohimbine or the combination GR127935 and
yohimbine in vagosympathectomized dogs. *, P<0.05 vs response in saline pre-treated animals. With permission from [73] Br. J. Pharmacol.
126: 585-594.

interest. In contrast to sumatriptan and naratriptan, active
metabolites have been reported for zolmitriptan, rizatriptan
and eletriptan. It is not known, whether and if so, to what
extent, the metabolites contribute towards the amount and
duration of therapeutic activity and recurrence rates. We are
not aware whether the metabolism of almotriptan and
frovatriptan results in the formation of active metabolites.
coronary artery or human saphenous vein to produce
constriction [99]. Indeed, eletriptan was less potent to
produce coronary vasoconstriction than sumatriptan, but both
sumatriptan and eletriptan were equipotent to produce
meningeal vasoconstriction. Although both drugs are
contraindicated in patients with coronary artery disease, they
have a limited propensity to produce coronary effects in
healthy subjects [98].

CORONARY VASCULAR EFFECTS OF TRIPTANS

In the human coronary artery, 5-HT2 receptors are more
important, but about 20-30% response is mediated by 5-HT1
receptors [95]. Accordingly, sumatriptan moderately
constricts the human coronary artery, both in vivo [96] and
in vitro [98]. That is why this drug is not recommended in
patients with coronary artery disease. The other second-
generation triptans are slightly more potent (except
eletriptan), but show similar efficacy [79]. Recently, it has
been shown that eletriptan shows craniovascular selectivity
for the human middle meningeal artery over the human
FUTURE TRENDS IN THE EFFICACY OF
ANTIMIGRAINE DRUGS
It is undeniable that the cranial vasoconstrictor activity of
sumatriptan and the second-generation triptans, mediated by
the 5-HT1B receptor, is associated with their efficacy in the
acute treatment of migraine [18,19]. Unfortunately, the
5-HT1B receptor, being not exclusively confined to cranial
blood vessels, is most likely also responsible for the
moderate hypertension and coronary constriction noticed
with these drugs. Therefore, in an attempt to avoid coronary
80 Current Vascular Pharmacology, 2003, Vol. 1, No. 1
Fig. (5). Receptor binding profile of some triptans at 5-HT1B, 5-HT1D and 5-ht1F receptors. Taken from [76-80]
vasoconstriction at least four new avenues are being
explored: (i) 5-HT1D receptor agonists; (ii) 5-ht1F receptor
agonists; (iii) 5-HT7 receptor antagonists; and (iv) blockade
of receptors for CGRP and substance P.
5-HT1D Receptor Agonists
A series of isochroman-6-carboxamide derivatives,
including PNU-109291, have been described as highly
selective 5-HT1D receptor agonists (pKi values: 5.2 and 9.0 at
5-HT1B and 5-HT1D receptor, respectively) [61] (see Table
1). PNU-109291 is devoid of carotid vasoconstrictor effect in
the anaesthetised cat, but potently inhibits dural plasma
extravasation in the guinea-pig [61]. Moreover, these 5-HT1D
receptor agonists do not produce vasoconstriction in in vivo
(canine external and internal carotid bed [100]) or in vitro
(cerebral arteries; [101]) preparations. More recently, it has
been shown that PNU-142633 is ineffective in patients with
migraine [17]. Clearly, inhibition of dural plasma
extravasation by itself is not predictive of antimigraine
activity.
5-ht1F Receptor Agonists
Two potent 5-ht1F receptor agonists, LY344864 (pKi
values: 6.3, 6.2 and 8.2 at 5-HT1B, 5-HT1D and 5-ht1F
Villalón et al.
receptor, respectively [62]) and LY334370 (pKi values: 6.9,
6.9 and 8.8 at 5-HT1B, 5-HT1D and 5-ht1F receptor,
respectively [62]) have been described. Both compounds
potently inhibit dural plasma protein extravasation [62,63],
but are devoid of vasoconstrictor activity [101]. Together
with the fact that SB224289, which displays little affinity at
the 5-ht1F receptor [72], completely antagonises sumatriptan-
induced external carotid vasoconstrictor effects [73], it is
evident that the 5-ht1F receptor is not involved in the
vasoconstrictor effects of sumatriptan and the second-
generation triptans. It therefore implies that if LY334370 turns
out to be effective in migraine at doses devoid of 5-HT1B/1D
receptor interaction, the mechanism of action will not be via
cranial vasoconstriction. In fact, it has recently been reported
that LY334370 is clinically effective to abort migraine attacks
[16]. However, it has to be emphasised that LY334370
displayed antimigraine activity at doses that may interact
with extracranial vasoconstrictor 5-HT1B receptors [16]. In
the absence of the importance of dural plasma protein
extravasation (see above), further experiments will be
needed to explain the efficacy of LY334370.
5-HT7 Receptor Antagonists
Methysergide and lisuride, prophylactic antimigraine
drugs, have high affinity for 5-HT7 receptors [47]. In
Migraine: Pathophysiology, Pharmacology, Treatment and Future Trends
Fig. (6). Plasma half-life (t1/2), time to reach the maximum concentration (t max) and bioavailability of several triptans after oral administration
of sumatriptan (100 mg), zolmitriptan (5 mg), naratriptan, (2.5 mg), Rizatriptan, (10 mg), eletriptan (40 mg), almotriptan (12.5 mg) and
frovatriptan (2.5 mg). Taken from [81-90,110,91-94]
addition, it has been shown that 5-HT7 receptors mediate
vasodilator responses in several vascular tissues [102]
including the canine external carotid bed [70]. Thus, it would
be expected that selective antagonists at 5-HT7 receptors
might have antimigraine properties, although this remains to
be determined.
Blockade of Receptors for CGRP and Substance P
Electrical stimulation of the trigeminal ganglion produces
release of potent vasodilator peptides such as substance P
and CGRP [103]. Further evidence suggests that during an
attack of migraine an increase in plasma levels of CGRP is
observed [104]. The release of CGRP is blocked by
dihydroergotamine and sumatriptan [103], indicating that the
blockade of this mechanism could be another strategy to
develop antimigraine drugs. Recently, it has been shown that
the CGRP antagonist, BIBN4096BS, potently and
dose-dependently inhibited the increases in facial blood flow
induced by electrical stimulation of the trigeminal ganglion
[105]. These findings, in conjunction with the ability of
BIBN4096BS to antagonise CGRP-induced vasorelaxation
of the human temporal artery [106] and porcine carotid
arteriovenous anastomosis [107] strongly suggest that
Current Vascular Pharmacology, 2003, Vol. 1, No. 1 81
blockade of vascular CGRP receptors may have potential
therapeutic usefulness in the treatment of migraine. In
addition, a new nonpeptide CGRP antagonist, SB-273779,
which blocked the CGRP-induced hypotension in
anaesthetised rats [108], represents an opportunity to analyse
its potential antimigraine activity.
Lastly, it has been shown that lanepitant, a very potent
antagonist of the receptor for substance P (an NK1 receptor
antagonist), was not clinically effective in preventing
migraine [109], although it inhibited the neurogenic dural
inflammation. Thus, these results suggest that blockade of
NK1 receptors is not a good strategy to abort an attack of
migraine.
CONCLUDING REMARKS
Migraine treatment has been described over the centuries
(even millennia!). Their writings, from ancient times to the
present, mirror the evolution of scientific thought, with
migraine metamorphosing from a disease attributed to
supernatural causes to a molecular disorder. With this long
history, notwithstanding, it is extremely surprising that
effective antimigraine drugs had been, until very recently,
82 Current Vascular Pharmacology, 2003, Vol. 1, No. 1
limited in number. Indeed, in comparison to other areas of
pharmacology, the therapeutic approaches to headache have
advanced minimally over the past 100 years. Fortunately, in
the last decades, there have been big steps in understanding
the pathophysiology of migraine and in the development of
antimigraine drugs. Evidently, new approaches need to be
explored (e.g. drugs that inhibit the trigemino-vascular
system) in order to obtain selective drugs with less
cardiovascular adverse effects.
ACKNOWLEDGEMENTS
The authors thank the Consejo Nacional de Ciencia y
Tecnología (Mexico City, Mexico) for support of this work.
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