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mise à jour du 13 mars 2003
Funct Neurol
2000;15 Suppl 3:171-81
Dopamine involvement in the migraine attack
Fanciullacci M, Alessandri M, Del Rosso A
Department of Internal Medicine, Headache Centre, University of Florence, Italy


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.


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.


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.


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.


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.


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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