mise à jour du 13 mars 2003
Clin Neuropharmacol 1997 Feb; 20(1); 36-4
Dopamine hypersensitivity in migraine: role of the apomorphine test
Cerbo R, Barbanti P, Buzzi MG, Fabbrini G, Brusa L, Roberti C, Zanette E, Lenzi GL
Department of neurological sciences, University La Sapienza, Rome


Clinical and pharmacological evidence suggests that dopamine (DA) is involved in migraine pathogenesis. Most prodromal and accompanying symptoms (mood changes, yawning, food craving, nausea, vomiting, drowsiness, and hypotension) may be related to dopaminergic activation. Several drugs acting on DA receptors (e.g., ergotamine, domperidone, lisuride, dihydroergocriptine, and flunarizine) are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration when compared with normal subjects. Thus, it has been argued that migraine is characterized by a DA postsynaptic receptors hypersensitivity, probably due to a chronic deficiency of DA release by presynaptic neurons.

Acute administration of apomorphine, a D1-like and D2-like agonist acting at nanomolar doses on DA presynaptic receptors and at micromolar doses also on DA postsynaptic receptors, has been considered to be an unmasker of dopaminergic hypersensitivity and to act as a migraine trigger in migraineurs. However, conflicting results have been reported so far. Our study was therefore designed to investigate the activation threhold of DA receptors in selected migraine population by subcutaneus apomorphine at increasing doses. [...]


The present study indicates that subcutaneous apomorphine up to a dose of 10 µg/kg does not induce either headache or spontaneous-like migraine symptoms in migraineurs. Our data confirm those of previous studies reporting no headache following apomorphine administration at doses of 0.005 µg/kg s.c. and 100 µg s.l., but are in contrast with others reporting typical migraine attacks or prodromal symptoms following 100 µg s.l.. These conflicting results may be due to the different doses or routes of administration used or to the inclusion criteria. Pharmacokinetic factors, however, are unlikely to account for the lack of headache in our patients. In tact, intravenous, subcutaneous, transdermal, and sublingual routes of apomorphine administration provide comparable volume of distribution, clearance, and half-life of elimination. On the other hand, since migraine studies may be biased by the heterogeneity of patients as regards age, sex, attack frequency, illness duration, therapy, or concomitant diseases, we studied a homogeneous migraine population in headache-free period, excluding drug-abusers and patients with chronic migraine. In addition, since migraineurs are very sensitive to pharmacological stimulation in the 12-24 h following a migraine attack, patients were studied at least 4 days after the last attack.

This study nevertheless confirms that migraineurs are hypersensitive to dopaminergic stimulation. 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/kg1/ than postsynaptic ones (>30µg/kg). It is noteworthy that in our study while the dose of 10 µg/kg induced, at most, yawning and drowsiness (presynaptic symptoms) in controls, the same dose caused also nausea and vomiting (postsynaptic symptoms) in migraineurs, thus demonstrating a lower activation threshold of DA recepton It is interesting to note that yawning and drowsiness, which were in any case more frequent in migraineurs than in controls, occurred immediately before nausea and vomiting, suggesting that apomorphine sequentially activated pre- and postsynaptic receptors. The administration of domperidone, a peripheral DA receptor antagonist, prevented the occurrence of peripheral dopaminergic symptoms (nausea, vomiting, dizziness, sweating) in migraineurs but did not affect central dopaminergc ones (yawning, drowsiness).

Taken as a whole, these findings support the view that doparninergic hypersensitivily is a specific migraine trait. Indeed, if we exclude the algie phase, most behavioral and vegetative symptorns characterizing the migraine syndrome are mediated by dopaminergic activation. Furthermore, one study recently reported an increased density in DA D5 receptors on peripheral blood lymphocytes in migraine patients. Flowever, the lack of headache in our study indicates that the stimulation of DA receptors is not itself a migraine trigger. Siculeri suggest that apomorphine induces migraine by stimulating hypersensitive DA presynaptic receptors located on DAergic and opiatergic endings, leading to a further decrease in neurotransinitters release. Migraine pathogenesis is, however, probably moch more complex and involves several other neurotransmitters (Serotonin, glutamate, peptides), different brain areas (brainstem, hypothalamus, thalamus, cerebral cortex), and neuronal pathways, and implies a complex integration of vascular and myofascial nociceptive inputs converging on brainstem together with supraspinal facilitatory and inhibitory control.

We conclude, therefore, that apomorphine at the dose of 10 µg/kg is able to unmask the dopaminergic hypersensitivity in migraineurs, but does not act as a migraine trigger. The severity of the induced symptoms, however, suggests that il should not be routincly used as a test for diagnosis in headache patients in clinical practice

  • Bès A et al Hypersensibilité dopaminergique dans la migraine: un test diagnostique ? La Nouvelle Presse Médicale1982; 11; 19
  • Blau JN Migraine postdromes: symptoms after attacks Cephalagia 1991 Nov; 11; 5; 229-31
  • Blin O, Azulay JP, Masson G, Aubrespy G, Serratrice G Apomorphine-induced yawning in migraine patients: enhanced responsiveness Clin Neuropharmacol 1991 Feb; 14; 1; 91-5
  • Cerbo R, Barbanti P, Buzzi MG, Fabbrini G, Brusa L, Roberti C, Zanette E, Lenzi GL Dopamine hypersensitivity in migraine: role of the apomorphine test Clin Neuropharmacol 1997 Feb; 20; 1; 36-4
  • Del Bene E, M Poggioni Video assessment of yawning induced by sublingual apomorphine in migraine Headache 1994; 34; 9; 536-8
  • Del Zompo M Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope Headache 1995; 35; 222-224
  • Del Zompo M Association between dopamine receptor genes and migraine without aura in a Sardinian sample Neurology 1998; 51; 3; 781-6
  • Fanciullacci M, Alessandri M, Del Rosso A Dopamine involvement in the migraine attack. Funct Neurol 2000; 15 Suppl 3:171-81
  • Heinrichs L Linking olfaction with nausea and vomiting of pregnancy, recurrent abortion, hyperemesis gravidarum, and migraine headache Headache 2003; 43; 3; 304-5
  • Jacome D Compulsive yawning as migraine premonitory symptom Cephalalgia 2001 Jun; 21; 5; 623-5
  • Jacome D Primary yawning headache Cephalalgia 2001 Jul; 21; 6; 697-699
  • James MF,Smith J M et al Cortical spreading depression and migraine: new insights from imaging? Trends in Neurosciences May 2001; vol 24; n 5; p 266-271
  • Loder A What is the evolutionary advantage of migraine ? Cephalalgia 2002; 22; 624-632
  • Peres MF et al Hypothalamic involvement in chronic migraine J Neurol Neurosurg Psychiatry 2001; 71; 747-751
  • Peroutka SJ Dopamine and migraine Neurology 1997 Sep; 49; 3; :650-6
  • Pietrobon D, J Sriessnig Neurobiology of migraine Nature Neurosciences Reviews may 2003; vol 4; n°5; p386-398
  • Sabatini U et al Migraine attacks induced by subcutaneous apomorphine in two migrainous parkinsonian patients Clinical Neuropharmacology1990; 13; 3; 264-267
  • Szechtman H et al Sensitization and Tolerance to Apomorphine in Men: Yawning, Growth Hormone, Nausea, and Hyperthermia Psychiatry Research 1988, 23, 245-255