Dopamine involvement in the migraine attack Fanciullacci M, Alessandri M, Del
Rosso A Department of Internal Medicine, Headache Centre, University of
Florence, Italy

Chat-logomini

    Clinical evidence and recent genetic findings seem to indicate an
involvement of dopamine in the pathophysiology of the migraine attack.
Prodromal symptomatology (mood changes, yawning, drowsiness, food craving),
accompanying symptoms (nausea, vomiting, hypotension) and postdromal symptoms
(mood changes, drowsiness, tiredness) may be related to dopaminergic
activation. The dopaminergic system could also play a role in the headache
phase, either by taking part in nociception mechanisms, or by regulating
cerebral blood flow. A body of pharmacological findings seems to support this
involvement. Migraine patients, between attacks, show a higher responsiveness
to acute administration of dopaminergic agents. Apomorphine administration
induces in migraineurs more yawns as well other dopaminergic symptoms e.g.
nausea, vomiting, dizziness. Migraine has been associated with hypotension
and, occasionally, with syncope. Bromocriptine causes severe orthostatic
syndrome in migraine patients. Both piribedil and apomorphine markedly
increase cerebral blood flow of migraine patients, thus indicating enhanced
responsiveness of dopamine receptors which are involved in cerebral blood
flow regulation. Interictal dopaminergic hypersensitivity has also been
demonstrated by means of neuroendocrine tests. Altered dopaminergic control
of prolactin secretion exists in migrainous women. L-deprenyl, a MAO-B
inhibitor, is significantly more effective in reducing prolactin levels in
migraineurs than in controls. Taken together, these findings support the view
that hypersensitivity of peripheral and central dopaminergic receptors is a
specific migraine trait. Finally, a high density of lymphocytic D5 receptors
has been found in migraine sufferers, thus suggesting their upregulation.
Therefore, the hypothesis that dopaminergic activation is a primary
pathophysiological component in certain subtypes of migraine, namely those
characterised by marked dopaminergic symptomatology, has been advanced. From
this perspective, a blockade of dopaminergic hyperresponsive receptors can be
considered as a rationale for the therapy of migraine.   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.

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