The dopamine theory of migraine pathogenesis, first proposed by F. Sicuteri in 1977, has attracted renewed interest after an increased frequency of the dopamine D2 receptor (DRD2) gene allele NcoI C was found in patients with migraine with aura. Therefore we reviewed the relevant literature. The most compelling argument favoring an interictal hypersensitivity of dopamine receptors in migraineurs stems from pharmacologic studies of the gastric and autonomic effects of dopaminergic agents such as apomorphine, but none of these studies was blinded and placebo-controlled. Various DRD2 antagonists abort migraine attacks after parenteral administration, while mere is circumstantial evidence that dopamine agonists may be useful for prophylaxis. Most drugs used in these trials, however, lack selectivity for dopamine receptors. Both in pharmacological and therapeutic studies most patients had migraine without aura. We conclude that data suggesting a primary role for the dopaminergic system in migraine pathogenesis are unconvincing. Based on well established interactions between central amines, a reduced release of serotonin between attacks could lower dopamine release which would lead to receptor hypersensitivity.
HumphreyPPFeniukWMarriottASTannerRJJacksonMRTuckerML.
Preclinical studies on the anti-migraine drug, sumatriptan.
Eur Neurol1991;
31:
282–90
2.
FerrariMDSaxenaPR.
On serotonin and migraine: a clinical and pharmacological review.
Cephalalgia1993;
13:
151–65
3.
WangWTimsit-BerthierMSchoenenJ.
Intensity dependence of auditory evoked potentials in migraine: an indication of cortical potentiation and low serotonergic neurotransmission?
Neurology1996;
46:
1404–9
4.
SicuteriF.
Dopamine, the second putative protagonist in headache.
Headache1977;
17:
129–31
5.
PeroutkaSJWilhoitTJonesK.
Clinical susceptibility to migraine with aura is modified by dopamine D2 receptor (DRD2) NcoI alleles.
Neurology1997;
49:
201–6
6.
Del ZompoMCherchiAPontiMLaiMPiccardiMP.
Association study between dopamine D2, D3 and D4 receptor genes and migraine without aura in a Sardinian sample.
Cephalalgia1997;
17:
329
7.
HydeTMKnableMBMurrayAM.
Distribution of dopamine D1-D4 receptor subtypes in human dorsal vagal complex.
Synapse1996;
24:
224–32
8.
KohliJDGlockDGoldbergLI.
Selective DA2 versus DA1 antagonist activity of domperidone in the periphery.
Eur J Pharmacol1983;
89:
137–41
9.
SicuteriFBonucciMCangiFPietriniUFanciullacciM.
Syncope and dopamine-receptor hyperreactivity: myths and facts about basilar artery migraine.
In:
CarrollJDPfaffenrathVSjaastadO, editors.
Migraine and beta-blockade.
Molndal:
Hassle AB,
1985:
147–60
10.
ChudlerEHDongWK.
The role of the basal ganglia in nociception and pain.
Pain1995;
60:
3–38
11.
PaalzowGHM.
L-Dopa induces opposing effects on pain in intact rats: (-)-sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses.
J Pharmacol Exp Ther1992;
263:
470–9
12.
MileyDPAbramsAAAtkinsonJHJanowskyDS.
Successful treatment of thalamic pain with apomorphine.
Am J Psychiatry1978;
135:
1230
13.
GrantRBehanPO.
Resistant thalamic pain treated by levodopa.
Br Med J1984;
289:
1272
14.
KernbaumSHauchecorneJ.
Administration of levodopa for relief of herpes zoster pain.
J Am Med Assoc1981;
246:
132–4
15.
NuttJGCarterJH.
Sensory symptoms in Parkinsonism related to central dopaminergic function.
Lancet1984;
ii:
456–7
LorentzIT.
A survey of headache in Parkinson's disease.
Cephalalgia1989;
9:
83–6
18.
Van HiltenJJ.
The migraine-dopamine link: do migraine and Parkinson's disease coexist?
Clin Neurol Neurosurg1992;
Suppl 94:
168–70
19.
SabatiniURascolORascolAMontastrucJ.
Migraine attacks induced by subcutaneous apomorphine in two migrainous Parkinsonian patients.
Clin Neuropharmacol1990;
13:
264–7
20.
GuanXMMcBrideWJ.
Serotonin microinfusion into the ventral tegmental area increases accumbens dopamine release.
Brain Res Bull1989;
23:
541–7
21.
BoulenguezPRawlinsJNChauveauJJosephMHMitchellSNGrayJA.
Modulation of dopamine release in the nucleus accumbens by 5HT1B agonists: involvement of the hippocampo-accumbens pathway.
Neuropharmacology1996;
35:
1521–5
NissbrandtHWatersNHjorfhS.
The influence of serot-oninergic drugs on dopaminergic neurotransmission in rat substantia nigra, striatum and limbic forebrain in vivo.
Naunyn Schmiedebergs Arch Pharmacol1992;
346:
12–9
SaitoHMatsumotoMTogashiHYoshiokaM.
Functional interaction between serotonin and other neuronal systems: focus on in vivo microdialysis studies.
Jpn J Pharmacol1996;
70:
203–5
Del BeneEPoggioniMDe TommasiF.
Video assessment of yawning induced by sublingual apomorphine in migraine.
Headache1994;
34:
536–8
28.
Del ZompoMLaiMLoiVPisanoMR.
Dopamine hypersensitivity in migraine: role in apomorphine syncope.
Headache1995;
35:
222–4
29.
CerboRBarbantiPBuzziMGFabbriniGBrusaLRobertiCDopamine hypersensitivity in migraine: role of the apomorphine test.
Clin Neuropharmacol1997;
20:
36–41
30.
FanciullacciMMichelacciSCurradiCSicuteriF.
Hyperre-sponsiveness of migraine patients to the hypotensive action of bromocriptine.
Headache1980;
20:
99–102
31.
SerraGColluMGessaGL.
Yawning is elicited by D2 dopamine agonists but is blocked by D1 antagonists, SCH 23390.
Psychopharmacology1987;
91:
330–3
32.
BèsACometBDupuiPGuellAArne-BèsMCGéraudG.
Antimigraine drugs and dopamine hypersensitivity.
In:
AmeryWKVan NuetenJMWauquierA, editors.
The pharmacological basis of migraine therapy.
London:
Pitman Press,
1984202–12
33.
CalabresiPSilvestriniMStrattaFCupiniLMArigoGAtzeiGP1-Deprenyl test in migraine: neuroendocrinological aspects.
Cephalalgia1993;
13:
406–9
34.
International Headache Society.Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain.
Cephalalgia1988;
8Suppl 7:
1–96
35.
PradalierALaunayJMDryJDreuxCArtigouC.
Migraine commune. Variations des catécholamines conjuguées et non conjuguées.
Presse Med1985;
14:
583–5
36.
D'AndreaGWelchKMANagel-LeibySGrunfeldSJosephR.
Platelet catecholamines in migraine.
Cephalalgia1989;
9:
3–5
37.
Nagel-LeibySWelchKMAD'AndreaGGrunfeldSBrownE.
Event-related slow potentials and associated catecholamine function in migraine.
Cephalalgia1990;
10:
317–29
38.
KovácsKBorsLTóthfalusiLJelencsikIBozsikGyKerényiL.
Cerebrospinal fluid (CSF) investigations in migraine.
Cephalalgia1989;
9:
53–7
39.
CastilloJMartinezFSuarezCNaveiroJLemaMNoyaM.
Cerebrospinal fluid tyrosine and 3,4-dihydroxyphenyiacetic acid levels in migraine patients.
Cephalalgia1996;
16:
56–61
40.
BarbantiPBronzettiERicciACerboRFabbriniGBuzziMGIncreased density of dopamine D5 receptor in peripheral blood lymphocytes of migraineurs: a marker for migraine?
Neurosci Lett1996;
207:
73–6
41.
Timsit-BerthierMMantanusHMarissiauxPAnsseauMDoumontAGeenenVCNV and dopamine receptor reactivity: correlations with the apomorphine test.
Electroen-cephalogr Clin Neurophysiol Suppl1986;
38:
403–5
42.
SchoenenJMaertens de NoordhoutATimsit-BerthierMTimsitM.
Contingent negative variation (CNV) as a diagnostic and Physiopathologic tool in headache patients.
In:
RoseClifford, editor.
Migraine.
Proc 5th Int Migraine Symp, London 1984.
Basel:
Karger,
1985:
17–25
43.
LenarduzziPTimsit-BerthierMGérardPSchoenenJVariation contingent negative (VCN) dans la migraine avec aura ("migraine classique") en période intercritique.
Société Française d'études des migraines et céphalées. Association pour la Neuro-psyco-pharmacologie
1988:
17–8
44.
BöckerKBETimsit-BerthierMSchoenenJBruniaCHM.
Contingent negative variation in migraine.
Headache1990;
30:
604–9
45.
KroppPGerberWD.
Contingent negative variation—findings and perspectives in migraine.
Cephalalgia1993;
13:
33–6
46.
KroppPGerberWD.
The predictable migraine attack.
News in Headache1994;
4:
3
47.
KroppPGerberWD.
Contingent negative variation during migraine attack and interval: evidence for normalization of slow cortical potentials during the attack.
Cephalalgia1995;
15:
123–8
48.
KroppPGerberWDRepasV.
Can migraine attacks be predicted by evaluation of contingent negative variation?
Cephalalgia1997;
17:
266
49.
SchoenenJWangWAlbertADelwaidePJ.
Potentiation instead of habituation characterizes visual evoked potentials in migraine patients between attacks.
Eur J Neurol1995;
2:
115–22
50.
ÁfraJProietti CecchiniADe PasquaVAlbertASchoenenJ.
Visual evoked potentials during long-lasting pattern-reversal stimulations in migraine.
Brain1997
(in press)
51.
WangWSchoenenJTimsit-BerthierM.
Cognitive functions in migraine without aura between attacks: a psychophysiological approach using the “oddball” paradigm.
Neurophysiologie Clinique1995;
25:
3–11
52.
EversSBauerBSuhrBHusstedtIWGrotemeyerKH.
Cognitive processing in primary headache: a study on event-related potentials.
Neurology1997;
48:
108–13
53.
OnofrjMBodis-WollnerI.
Dopaminergic deficiency causes delayed visual evoked potentials in rats.
Ann Neurol1982;
11:
484–90
54.
YamamotoKHaginoKMorojiTIshiiT.
Habituation failure of skin conductance response after intraventricular administration of 6-hydroxydopamine in cats.
Expérimenta1984;
40:
344–5
55.
ImperatoACabibSPuglisi-AllegraS.
Repeated stressful experiences differently affect the time-dependent responses of the mesolimbic dopamine system to the stressor.
Brain Res1993;
601:
333–6
56.
VolansGN.
The effect of the metoclopramide on the absorption of effervescent aspirin in migraine.
Br J Clin Pharmacol1975;
2:
57–63
57.
Ross-LeeLMEadieMJHeazlewoodVBochnerFTyrerJH.
Aspirin pharmacokinetics in migraine. The effect of metoclopramide.
Eur J Clin Pharmacol1983;
24:
277–35
58.
TokolaRA.
The effect of metoclopramide and prochlorperazine on the absorption of effervescent paracetamol in migraine.
Cephalalgia1988;
8:
139–47
59.
TokolaRAKangasniemiPNeuvonenPJTokolaO.
Tolfenamic acid, metoclopramide, caffeine and their combination in the treatment of migraine attacks.
Cephalalgia1984;
4:
253–63
60.
McGregorAWilkinsonMBancroftK.
Domperidone plus paracetamol in the treatment of migraine.
Cephalalgia1993;
13:
124–7
61.
Tfelt-HansenPOlesenJ.
Effervescent metoclopramide and aspirin (Migravess) versus effervescent aspirin or placebo for migraine attacks: a double-blind study.
Cephalalgia1984;
4:
107–11
62.
TekDSMcClellanDSOlshakerJSAllenCLArthurDC.
A prospective, double-blind study of metoclopramide hydrochloride for the control of migraine in the Emergency Department.
Ann Emerg Med1990;
19:
1083–7
63.
HughesJB.
Metoclopramide in migraine treatment [Letter].
Med J Aust1977;
2:
580
64.
EllisGLDelaneyJDeHartDAOwensA.
The efficacy of metoclopramide in the treatment of migraine headache.
Ann Emerg Med1993;
22:
191–5
65.
CameronJDLanePLSpeechleyM.
Intravenous chlorpromazine vs metoclopramide in acute migraine headache.
Acad Emerg Med1995;
2:
597–602
66.
CoppolaMYealyDMLeiboldRA.
Randomized, placebo-controlled evaluation of prochlorperazine versus metoclopramide for emergency department treatment of migraine headache.
Ann Emerg Med1995;
26:
541–6
67.
HakkarainenHAllonenH.
Ergotamine vs metoclopramide vs their combination in acute migraine attacks.
Headache1982;
22:
10–12
68.
AmeryWYWaelkensJ.
Prevention of the last chance: an alternative pharmacological treatment of migraine.
Headache1983;
23:
37–8
69.
McEwenJIO'ConnorHMDinsdaleHB.
Treatment of migraine with intramuscular chlorpromazine.
Ann Emerg Med1987;
16:
758–63
70.
IsersonKV.
Parenteral chlorpromazine treatment of migraine.
Ann Emerg Med1983;
12:
756–8
71.
LaneRLRossR.
Intravenous chlorpromazine—preliminary results in acute migraine.
Headache1985;
25:
302–4
72.
BellRMotoyaDShuaibALeeMA.
A comparative trial of three agents in the treatment of acute migraine headache.
Ann Emerg Med1990;
19:
1079–82
73.
JonesJSklarDDoughertyJWhiteW.
Randomized double-blind trial of intravenous prochlorperazine for the treatment of acute headache.
JAMA1989;
261:
1174–6
74.
FisherH.
A new approach to emergency department therapy of migraine headache with intravenous haloperidol: a case series.
J Emerg Med1995;
13:
119–22
75.
LugaresiAMontagnaPGallasiRLugaresiE.
Extrapyramidal syndrome and depression induced by flunarizine.
Eur Neurol1988;
28:
208–11
76.
PicciniPNutiAPaolettiAMNapolitanoAMelisGBBonuccelliU.
Possible involvement of dopaminergic mechanisms in the antimigraine action of flunarizine.
Cephalalgia1990;
10:
3–8
77.
WöberCBrückeTWöber-BingölCAsenbaumSWesselyPPodrekaI.
Dopamine D2-receptor blockade and antimigraine action of flunarizine.
Cephalalgia1994;
14:
135–40
78.
LouisP.
A double-blind placebo controlled prophylactic study of flunarizine (Sibelium®) in migraine.
Headache1981;
21:
235–9
79.
CerboRCasacchiaMFormisanoRFelicianiMCusimanoGBuzziMGFlunarizine-pizotifen single dose, double-blind cross-over trial in migraine prophylaxis.
Cephalalgia1986;
6:
15–8
80.
LuckingHCOestreichWSchmidtRSoykaD.
Flunarizine vs propranolol in the prophylaxis of migraine: two double-blind comparative studies in more than 400 patients.
Cephalalgia1988;
Suppl 8:
21–6
81.
SoykaDTaneriZOestreichWSchmidtR.
Flunarizine i.v. in the acute treatment of common or classical migraine attacks a placebo-controlled double blind trial.
Headache1989;
29:
21–7
82.
PfaffenrathVOestreichWHaaseW.
Flunarizine (10 and 20 mg) i.v. versus placebo in the treatment of acute migraine attacks: a multi-centre double-blind study.
Cephalalgia1990;
10:
77–81
83.
Tfelt-HansenPHenryPMulderLJScheldewaertRGSchoenenJChazotG.
The effectiveness of combined oral lysine acetylsalicylate and metoclopramide compared with oral sumatriptan for migraine.
Lancet1995;
346:
923–6
84.
AnderschBHahnLWendestamCOhmanRAbrahamssonL.
Treatment of premenstrual syndrome with bromocriptine.
Acta Endocrinol1978;
88Suppl 216:
165–74
85.
AndersenANLarsenJFSteenstrupORSvendstrupBNielsenJ.
Effect of bromocriptine on the premenstrual syndrome: a double-blind clinical trial.
Br J Obstet Gynaecol1977;
84:
370–4
86.
HerzogAG.
Continuous bromocriptine therapy in menstrual migraine.
Neurology1997;
48:
101–2
87.
HerrmannWMHorowskyRDannehlKKramerULuratiK.
Clinical effectiveness of lisuride hydrogen maleate: a double-blind trial versus methysergide.
Headache1977;
17:
54–60
88.
SommervilleBWHerrmannWM.
Migraine prophylaxis with lisuride hydrogen maleate double-blind study of lisuride versus placebo.
Headache1978;
18:
75–9
89.
SancesGMartignoniMRosettinoGFioroniLMontorsiSRungeILisuride in menstrual migraine prophylaxis.
Cephalalgia1989;
9Suppl 10:
444–5
90.
NatteroGBialeLSaviL.
Lisuride and pizotifen in the treatment of migraine without aura.
Cephalalgia1991;
Suppl 11:
217–9
91.
CanonicoPLScapagniniUGenazzaniEZanottiA.
Dihy-droergokryptine (DEK) in the prophylaxis of common migraine: double-blind clinical study vs placebo.
Cephalalgia1989;
9Suppl 10:
445–7
92.
AvellaFPoliAAmbrosoliLGirardelloR.
The effectiveness of α-dihydroergocryptine in migraine prophylaxis: a double-blind clinical study vs placebo.
Cephalalgia1997;
17:
435
93.
FredianiFGrazziLZanottiAMaillandFZappacostaBMBussoneG.
Dihydroergokryptine versus dihydroergotamine in migraine prophylaxis: a double-blind clinical trial.
Cephalalgia1991;
11:
117–21
94.
PeroutkaSJ.
Dopamine and migraine.
Neurology1997;
49:
650–6
95.
WaelkensJ.
Dopamine blockade with domperidone: bridge between prophylactic and abortive treatment of migraine? A dose-finding study.
Cephalalgia1984;
4:
85–90
96.
AgrenHMeffordINRudorferMVLinnoilaMPotterWZ.
Interaction of neurotransmitter system. A non-experimental approach to 5-HIAA-HVA correlation in human CSF.
J Psychiatr Res1986;
20:
175–93
97.
OphoffRATerwindtGMVergouweMNvan EijkROefnerPJHoffmanSMGFamilial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4.
Cell1996;
87:
543–52
98.
TerwindtGMOphoffRASandkuijlLAvan EijkRHaanJFrantsRRInvolvement of the familial hemiplegic migraine gene on 19p13 in migraine with and without aura.
Cephalalgia1997;
17:
232
99.
CodignolaATarroniPClementiFPolioALovalloMCarboneECalcium channel subtypes controlling serotonin release from human small cell lung carcinoma cell lines.
J Biol Chem1993;
268:
26240–7
100.
ComingDEComingBGMuhlemanDDietzGShahbahramiBTastDThe Dopamine D2 receptor locus as a modifying gene in neuropsychiatrie disorders.
JAMA1991;
266:
1793–800
101.
NobleEP.
The gene that rewards alcoholism.
Sci Med1996;
3:
52–61
102.
BlumKNobleEPSheridanPJMontgomeryARitcheTJagadeeswaranPAllelic association of human dopamine D2 receptor gene in alcoholism.
JAMA1990;
263:
2055–60
103.
BolosAMDeanMLucas-DerseSRamsburgMBrownGLGoldmanD.
Population and pedigree studies reveal a lack of association between the dopamine D2 receptor gene and alcoholism.
JAMA1990;
264:
3156–60
104.
GejmanPVRamAGelernterJ.
No structural mutation in the dopamine D2 receptor gene in alcoholism or schizophrenia.
JAMA1994;
271:
204–8
105.
ChabriatHJoireJEDanchotJGripponPBousserMG.
Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicenter double-blind placebo-controlled study.
Cephalalgia1994;
14:
297–300
