Introduction : The pathogenetic
factors underlying migraine have not yet been
completely elucidated. However, migraine is also
regarded as a disease related to dysfunction of
central and peripheral "master neurotransmitter
systems" controlling cephalic pain and
vasomotility and other autonomic functions.
Serotonin has historically played an important
role in migraine pathogenesis; however, the
serotonin system may represent only one facet of
the monoamine involvement in migraine. In this
context, dopamine (DA) is able to modulate
nociception, autonomic responses and
vasoregulation, all of these functions being
involved in migraine pathophysiology.
In past decades, a body of clinical evidence
indicated a role of DA pathways in the chain of
successive events which result in a migraine
attack. These observations led to the idea that
migraine was linked to a DA receptor
hypersensitivity in certain brain and peripheral
regions related to migraine attack. This notion
has attracted renewed interest after the
emergence of genetic data showing an increased
frequency of certain alleles of the DA receptor
gene in migraine patients. The present paper
focuses on data indicating that alterations in
DA neurotransmission occur in migraine and
provides a rationale for a DA avenue in the
treatment of migraine.
POSSIBLE DOPAMINERGIC MECHANISMS IN THE
MIGRAINE ATTACK
Although headache remains the nucleus of
migraine episodes, five distinct migrainous
phases have been proposed by Blau: prodrome,
aura, headache, resolution, postdrome
(recovery). The symptoms of each phase have
their own characteristics and the tempo of
symptoms during each phase suggests diverse
pathophysiological mechanisms, therefore,
different treatments of the patient at different
phases may need to be sought.
Some prodromal symptoms and signs
indicate the involvement of DA in the
neurobiology of attack initiation, in
particular, at the hypothalamic site.
Physiological appetite is altered to craving and
then develops into nausea and, at times,
vomiting. The normal sleepwaking rhythm
changes to yawning and inappropriate
tiredness which increase during attacks endina
in sleep in young patients. Fluid retention and
thirst followed by increased diuresis also
suggest a dysregulation of kidney dopaminergic
modulation of sodium excretion.
The nausea and, at times, vomiting in the
headache phase of the attack is clearly a
clinical manifestation mediated by DA receptor
activation. In addition, orthostatic hypotension
and rarely lipothymia or syncope which may occur
during the attack seem to indicate the
involvement of DA regulation of the
cardiovascular system. Therefore, clinical
observations show that manifestations of the
migraine attack, in particular yawning,
emetic symptoms and hypotension, seem to
characterize the DA-induced migraine attacks
which are particularly frequent in a subgroup of
patients.
Recently, MRI performed in one patient during
visual aura of migraine highlighted bilateral
involvement of dopaminergic red nucleus and
substantia nigra. The nigro-striatal pathway is
involved in motor control and sensorimotor
integration. Although there is no supportive
human evidence, stimulation of red nucleus in
the rat induces analgesia. Therefore, abnormal
function of the red nucleus may be relevant to
the head pain experienced by the patients.
Nigrostriatal dysfunction may be associated with
pain, nausea, vomiting and other dysautonomic
features of the migraine attack.
HYPERRESPONSIVENESS TO DOPAMINERGIC DRUGS
IN MIGRAINE PATIENTS BETWEEN ATTACKS
Numerous investigations carried out with DA
agonists, which must be considered drug tools
capable of explaining DA-dependent function at
central and peripheral levels, have demonstrated
a hyperreactivity to dopaminergic receptor
activation in migraine patients.
Behavioral signs : Yawning and
drowsiness are common behavioral
manifestations which may precede, and at times
accompany the pain of a migraine attack. The
physiological role of yawning is still poorly
understood, but central dopaminergic pathways
are involved in the intricate mechanism
underlying, yawning.
Apomorphine. a selective D1 and D2 receptor
agonist, has been shown to induce yawning
in healthy volunteers. Apomorphine-induced
yawning and drowsiness result from DA
presynaptic receptor activation, whereas nausea
and vomiting result from DA postsynaptic
stimulation. In humans, DA presynaptic receptors
are characterized by a lower activation
threshold to apomorphine (10-20 µg/kg) with
respect to post-synaptic ones (30 µg/kg).
Therefore. apomorphine-induced yawning
may be useful in the evaluation of central
dopaminergic receptor sensitivity. Evidence from
different studies has shown that migraine
patients have an augmented behavioral response
to apomorphine. Subcutaneous apomorphine (5
µg/kg ) induced a higher number of yawns in
migraine patients-. In addition, by using an
audiovisual technique in order to evaluate
behavioral phenomena. it has been observed that
0.25 mg apomorphine, sublingually administered,
provokes a greater number of yawns
between 15 and 45 minutes after drug
administration in migraine patients. Also
different subcutaneous doses (2 or 10 µg)
of apomorphine (apomorphine test) have
demonstrated a DA hypersensitivity in migraine
patients. The dose of 10 µg/kg induced, at
most, yawning and drowsiness (presynaptic
symptoms) in controls, but the same dose also
caused nausea and vomiting (postsynaptic
symptoms) in migraineurs, thus demonstrating a
lower activation threshold of DA receptors.
Yawning and drowsiness occurred
immediately before nausea and vomiting,
suggesting that apomorphine sequentially
activated pre- and post-synaptic receptors. The
administration of domperidone prevented the
occurrence of peripheral dopaminergic symptoms
(nausea, vomiting, dizziness, sweating) in
migraineurs but did not affect central
dopaminergic ones (yawning, drowsiness).
Emetic response : The emetic response
is achieved by a group of brainstem nuclei,
including the nucleus tractus solitarius and
dorsal motor nucleus of the vagus. The nucleus
tractus solitarius is the primary central input
point for stimuli acting on the chemoreceptor
trigger zone located ni the area postrema. DA
was originally suggested as a mediator of emesis
and to be involved in gastrointestinal
hypomotility and delayed gastric emptying.
Numerous studies showed that apomorphine was
highly emetic in man and that gastrointestinal
motility was increased and various emetic
stimuli blocked by DA receptor antagonists. DA,
acting at the D2 receptor subtype, is thought to
be involved in the transmission of emetic
stimuli in the area postrema where cells are
exposed to non brain-penetrant substances
circulating in the blood, and behind the blood
brain barrier (BBB) in the nucleus tractus
solitarius. A high expression of the D2 family
receptors has been detected in the nucleus of
the solitary tract, in the dorsal nucleus of the
vaeus and in the area postrema.
The migraine headache is almost always
associated with gastrointestinal symptoms
ranging from lack of appetite to vomiting. These
gastrointestinal symptoms do not appear to be a
simple reaction to the pain of migraine, because
they may occur with comparatively mild
headaches, and nausea may precede headache.
These symptoms account for a possible
involvement of D2 receptors which mediate emesis
during the migraine attack. Migraine sufferers
tested in the headache-free phase are
hypersensitive to the emetic effect of different
dopaminergic agents such as apomorphine, L-Dopa,
Lisuride and piribedil. Infact, apomorphine (l
mg i.m.), oral L-Dopa (500 mg) (26), and
piribedil (0. 1 mg/kg i.v.) provoked enhanced
emetic response (nausea, vomiting) in migraine
patients.
Hypopotension
:
Even though DA may directly affect the
arterial circulation, including cerebral
arteries through specific receptors located ou
the smooth muscle cells of the vascular wall,
the main mechanism involved in the DA regulation
of the cardiovascular system is represented by
the peripheral D2 receptors located
presynaptically on sympathetic nerves and
ganglia where they inhibit the release of
noradrenaline. The stimulation of these
receptors inhibits either the central tonic
action of the vasomotor center or the peripheral
noradrenaline release from vascular and heart
sympathetic nerves.
During interictal periods, a single oral dose
(2.5 mg) of bromocriptine causes in migraine
patients a significant and prolonged reduction
of lying and orthostatic blood presure, whereas
in healthy volunteers the hypotension is
moderate and transient. When bromocriptine is
administered to migraine patients suffering from
syncopes during spontaneous attacks, the
reduction of the mean arterial pressure is so
intense that it induces a presyncopal status. It
was observed that in these patients, presyncopal
phenomena following bromocriptine intake are
always correlated with a reduction of the blood
pressure in the standing position due to an
impairment of the postural reflex. The
hypotensive reaction following bromocriptine
administration can be prevented or antagonized
by treatment with domperidone, thus suggesting
that the effect is mediated by DA receptors
located outside the BBB. In a case report, the
administration of apomorphine at a dosage (370
µg i.m.) which generally has no effect in
normal subjects was able to trigger dramatic non
painful autonomic phenomena (nausea,
yawning, etc.) and cardioinhibitory
syncope. It cannot be ruled out that, in
migraine, the dopaminergic mediated inhibition
of sympathetic tonus may be amplified by the
described impairment of the activity of the
noradrenergic nerves.
Also, cerebral blood flow studies indicate
that migraineurs have increased sensitivity of
DA receptors located in cerebral vasculature.
Piribedil, a dopaminergic agonist which easily
crosses the BBB, administered by infusion (0. 1
mg/kg over 30 minutes) provokes in migraineurs a
marked increase of cerebral blood flow,
hypotension, nausea and vomiting. The
migraineurs were only able to tolerate less than
half the piribedil dose tolerated by controls.
Therefore, the migraine subject exhibits a
dopaminergic vascular hypersensitivity at brain
level (cerebral blood flow increase) as well as
at peripheral level (blood pressure
decrease).
Increased response of cerebral blood flow was
also observed after apomorphine administration.
By using transcranial doppler monitoring,
migraineurs, after subcutaneous apomorphine (5
µg and 10 µg/kg) administration.
showed dose-related increases in systolic
velocity and mean velocity, associated with a
decrease in pulsatility index, when compared
with controls and tension-type headache
patients.
Dopamine-induced migraine attack
Some studies have reported that stimulation
of DA receptors is a migraine trigger. Low doses
of DA agonists, quite rarely effective in
healthy subjects, provoke in migraineurs several
of the symptoms and signs that typically precede
or accompany a migraine attack. In fact
apomorphine (100 µg sublingually), lisuride
(25 µg i.v.) and bromocriptine (2.5 mg
orally), as compared to placebos, precipitate
pain and extrapain manifestations similar to the
symptoms occurring in a spontaneous migraine
attack. Domperidone (10 mg i.v.) is capable of
preventing totally or partially, all of these
disturbances. except the headache. Otherwise,
haloperidol (0.5 in- i.v.) and tiapride (100 in-
i.v.) which are DA antagonisis able to cross the
BBB, also prevent headache. This suggests that
in the mechanism of migraine the dopaminergic
system rnay also be involved inside the BBB,
especially in generating pain.
In general, headache is not a common,
recognized side effect of the direct dopamine
alomsts used in the treatment of Parkinson's
disease. However, a low dose of apomorphine 1 mg
was reported to induce migrainous headache in
elderly individuals with a past history of
migraine who were undergoing treatment for
Parkinson's disease. On the contrary, another
study indicates that apomorphine does not act as
a migraine trigger. The drug provokes
yawning, drowsiness. nausea and vomiting,
but no headache was reported following
subcutaneous apomorphine administration. None of
the apomorphined-induced symptoms resermbled
those characterizing a spontaneous migraine
attack.
Altered prolactin response to
dopaminergically acting drugs
A body of data indicates that the
tuberoinfundibular dopaminergic system which
controls the secretion of prolactin (PRL) from
the pituitary gland is altered in migraine. The
beneficial effects of bromocriptine in relieving
the major symptoms of premenstrual migraine have
suggested the dopaminergic involvement of PRL
regulation in precipitating migraine. On the
other hand, alterations in PRL secretion have
also been detected by the administration of
several neuroactive drugs which interfere with
DA function. Reserpine (13 µg/kg i.v.), a
monoamine depletor, and benserazide (125 mg
orally), an inhibitor of aromatic amino acid
decarboxylase which decreases the concentrations
of peripheral DA, cause a more prolonged release
of PRL in migraineurs than in healthy controls.
Similar data were obtained after the
administration of sulpiride, a DA receptor
blocker crossing the BBB, at doses (15 mg/ml
i.v.) which only act at peripherai level. In
addition, it was observed that in the follicular
phase of migrainous women, PRL responses to
domperidone (4 mg i.v.) were greater than in
controls. Likewise, during the same phase of the
ovarian cycle, the inhibitory effects on PRL
secretion of nomifensine (200 mg orally), an
indirect DA agonist which blocks DA reuptake,
are less pronounced in migraineurs than in
controls. Taken together, these results indicate
an increased lactotroph PRL reserve in migraine.
The smaller inhibitory effect of nomifensine on
PRL secretion in migrainous subjects suggests a
decrease of DA avaliable for lactotrophin
receptors in the prejunctional
tuberoinfundibular DA neurons. This condition
may induce a supersensitivity of the lactotroph
DA receptors, regarded as postjunctional. which
could explain an increased PRL reserve
generating an enhanced response after the
addition of DA receptor blockers. It was shown
that. physiologically, estrogen titers modulate
the sensitivity of DA receptor blockers. The
altered response to dopaminergically acting
drugs is particularly evident in the follicular
phase of migraineurs. Also, the finding of a
blunted PRL response, observed in men with
migraine without aura, elicited by intravenous
administration of 50 µg or 200 µg
thyrotropin-releasing hormone (TRH). may account
for a lactotroph DA receptor supersensitivity.
Physiologically, TRH is known to induce PRL
release by the activation of calcium-dependent
intracellular mechanisms. On the other hand, the
activation of D2 receptors by DA seems to
block-calcium influx into the lactotroph. In
migraine, it may be assumed that owing to D2
receptor supersensitivity, the dopaminergic
inhibitory effects prevail over the
TRH-releasing action. TRH administration is,
therefore, unable to show the existence of an
enhanced intracellular PRL reserve, which can be
demonstrated when D2 receptor blockers are
administered.
More recently another neuroendocrine study
has confirmed in migraine a hyperreactive
central DA system which regulates prolactin
secretion. It was observed that 1-deprenyl (5
mg), a MAO-B inhibitor which increases
endogenous DA by inhibiting its degradation
reduced circulating prolactin levels in female
migraine sufferers, but not in controls. The
effect was more pronounced in migraine with aura
than in migraine without aura.
INCREASED LYMPHOCYTE DA-RECEPTORS
The density and the pattern of D5 receptors
in peripheral blood lymphocytes have been
studied in a selected population of migraineurs.
The D5 receptor belongs to the Dl - like family.
In migraineurs a higher density of lymphocyte D5
receptors compared with controls was noticeable,
whereas the affinity of the radioligand was
unchanged. This finding suggests an upregulation
of these receptors in migraine.
THERAPEUTIC DA APPROACH TO
MIGRAINE
The possible DA dysfunction in migraine may
have practical consequences, prompting a more
in-depth study of drugs working on the
dopaminergic system in the treatment of
migraine. Since enhanced responsiveness of both
central and peripheral DA receptors appears to
be correlated with the clinical picture of the
migraine attack, a blockade or a desensitization
of DA supersensitive receptors can be considered
as a rationale for the therapy of migraine.
Numerous therapeutic data seem to support this
rationale.
Acute antimigraine treatment
Several DA antagonists are used in the acute
treatment of migraine, principally as antiemetic
and prokinetic agents. In fact, decreased
intestinal motility and slow gastric eemptying
are well known symptoms which occur during a
migraine attack. Prokinetic agents may therefore
be of value in the management of these migraine
symptoms, and may also promote the absorption of
antimigraine drugs that otherwise would pass
only slowly through the gastrointestinal tract
during a migraine attack. However, the rationale
for the use of dopamine antagonists in migraine
may be the correction of dopamine receptor
hypersensivity by blocking exaggerated DA
receptor responses which seem to occur in the
prodromal phase and during the attack. This
theoretical consideration suggested the use of
domperidone at the first appearance of the early
warning signals of a migraine attack. Forty mg
of domperidone prevented more than 60% of
attacks while placebo only 5%. The best response
was observed when domperidone was taken at least
6 hours and, even better 12 hours before the
attack. The patient must take his/her medication
as soon as he/she experiences the warning of an
impeding attack, even though it is sometimes
hard for physicians to get this message across
to the patients concerned. The domperidone
effect is dose-related. The piribedil test which
evaluates the peripheral doparninergic
sensitivity does not allow one to predict the
effectiveness of domperidone in a given
migrainous patien. Cisapride, a benzamide
gastrointestinal prokinetic agent that lacks DA
antagonist action, does not exert a preventive
action on the migraine attack. The fact that
domperidone penetrates the CNS indicates that a
significant amount of migraine symptomatology
results from the activation of peripheral DA
receptors. This finding is of particular
speculative interest but its application in
clinical practice is difficult.
Intravenous administration of metoclopramide
exerted a significant antimigraine action and
pain relief was obtained after 1 hour. In
addition, controlled trials have demonstrated
the efficacy of non selective D2 antagonisis
such as chlorpromazine, prochlorperazine and
haloperidol which arc used in emergency rooms
for the treatment of migraine attacks. For some
decades a combination of prochlorperazine
caffeine and indomethacin has been commonly used
in clinical practice in Italy for the treatment
of migraine attacks.
Prophylaclic anti migraine
treatment
The rationale for the long-term treatment
with DA agonists could be the induction of a
progressive DA receptor down regulatione. This
possibility, however. has not been tested by
assessing the sensitivity of migraineurs before
and after prophylactic treatment with agents
which exert a direct effect on DA
receptorsContinous bromocriptine (2.5mg,/tid)
decrezised refractory menstrual miraine attacks.
Lisuride and dihydroergocryptine are ergot
alkaloids with dose-dependent action on central
DRD2 receptors.
Lisuride at higher doses (0.05-0.075
µg/tid), where it acts as a DA agonist,
significantly reduced migraine attack frequency
and severity. Dihydroergocriptine (20 mg orally)
decreased the number of monthly headache days,
and was superior to placebo and to oral
dihydroergotamine for pain relief. Flunarizine,
a calcium antagonist with DA antagonist
properties has a well established efficacy in
migraine prophylaxis. Overall, some DA agonists
modify attack frequency more than severity.
Since all DA agonists used also act on other
receptors, the antimigraine effects might be due
to mechanisms unrelated to regulation of DA
receptors.
CONCLUDING REMARKS
In migraine the abnormal DA receptor
sensitivity has been attributed to a chronic
lack of available neurotransinitter at
prejunctional level. Since the dopaminergic
system is modulated by the serotoninegic system.
hypofunction of the dopaminergic system with
subsequent receptor hypersensitivity could
therefore be secondary to reduced serotonin
turnover.
The recent genetic findings seem to suggest a
primary abnormality of DRD2 receptors as a
substrate for a dopaminergic pathogenesis of
migraine.
A considerable accumulation of scientific
data over the last decade has helped to
attribute DA with a significant role in migraine
and has constituted an important element of the
-"migraine terrain" at least in a subgroup of
migraine patients. However, the precise
mechanisms underlying yhis disorder remain to be
elucidated. Therefore, further studies on DA
function by using more specific and direct tools
could enrich pathophysiological knowledge, as
well as the therapeutic perspective of
migraine.
