haut de page

mise à jour du 13 février 2003
Headache 1995;35;222-224
Dopamine Hypersensitivity in Migraine: Role in Apomorphine Syncope
Maria Del Zompo, Marina Lai, Vincenzo Loi, Maria Rosaria Pisano
From the Department of Neurosciences B.B. Brodie, Headache Conter and the Institute of Cardiology, University of Cagliari, Italy


There is some evidence supporting a potentiel role of hypersensitivity of the dopaminergic system in the pathogenesis of migraine. In this case report, we describe a syncopal episode in a patient with migraine without aura after the administration of a very low dose of apomorphine, a classical agonist of dopaminergic receptors. The absence of cardiovascular risk factors in this patient suggests that the clinical evant might have been caused by hypersensitivity of the dopaminergic system.
In spite of recent advances, the pathogenesis of migraine remains unknown. Clinical and experimental data suggest that hypersensitivity of dopamine (DA) receptors can play some role. Such a hypothesis is supported by the observation that the classical DA receptor agonist, apomorphine, often evokes in migraineurs the characteristic pain and associated phenomena of migraine, such as yawning, nausea, vomiting, hypotension, and syncope, at a dosage ineffective in control subjects?
Our group has long experience in the use of apomorphine in different neuropsychiatric disorders. In recent years, we have regularly used continuous subcutaneous infusions in Parkinson's and Huntington's disorders. In these cases, we first test the individual's sensitivity by a single intramuscular (IM) low dose of apomorphine to assess the lowest effective dose to be administered subcutaneously by continuous infusion without side effects such as nausea, vomiting, yawning, and hypotension. Moreover, because growth hormone (GH) is released by stimulation of hypothalamic D2 receptors, we also measure GH plasma levels after the apomorphine test to evaluate the effective stimulation of DA receptors. In our standard apomorphine test, the patient first receives an intramuscular placebo and 1 hour later, 6 µg/kg of apomorphine intramuscularly. Growth hormone levels at baseline and minutes after apomorphine administration are measured. Clinical evaluation and blood pressure measurement are performed immediately priorto the collection of each sample.
The reported efficacy of apomorphine given at low doses and chronically in migraine patients prompted us to consider continuous subcutaneous infusion of apomorphine in migraine patients resistant to prophylactic treatment with the aim of possibly desensitizing the DA system.
The patient was a 25-year-old woman suffering from migraine without aura since the age of 22. The pain was mainly unilateral, located in and around the right eye. Attacks lasted 24 hours and the frequency varied from three to four times per month. Pain was severe, disabling, and associated with nausea and vomiting, photophobia, and phonophobia. She also reported motion sickness characterized by nausea, vomiting, perspiration, and hypotension when traveling by car or ship. The patient was admitted to the Headache Center at the Department of Neurosciences in Cagliari, Italy.
She was resistant to conventional prophylactic treatments, and had been drug-free for 1 year prior to the test, which was undertaken after informed consent was obtained. Routine blood and urine tests, electroencephalogram, electrocardiogram, and a skull x-ray were normal. The test was performed during the morning. Blood pressure before the test was 120/80 mm Hg and the heart rate was 70 beats per minute. Baseline GH serum concentration was 4.0 ng/mL. After the placebo injection, the patient did not report any symptoms. Four minutes after the injection of µg apomorphine IM (6 µg/kg), the patient developed nausea, perspiration, yawning, epigastric distress, hyperpnea and weakness, followed by hypotension, pallor, diaphoresis, headache, nausea and vomiting, and subsequently loss of consciousness with shallow respiration, urinary incontinence, tonic movements of limbs, and upturned eyes. Unconsciousness lasted approximately 40 to 50 seconds. Soon after, blood pressure was 100/70 mm Hg and heart rate was 70 beats per minute.
During the loss of consciousness, the absences of a detectable pulse, unresponsiveness, and gasping respiration indicated the occurrence of cardiac arrest. The patient complained of nausea and vomiting and was treated with the potent selective DA 2 antagonist, L-sulpiride 100 mg IM, to counteract the effects of apomorphine. The patient was then admitted to the Institute of Cardiology, University of Cagliari. Blood pressure, heart rate, and a 12lead electrocardiogram were normal. Normality of cardiovascular parameters was established based on the following observations: negative family history of heart disease, normal physical examination and laboratory tests (including thyroid function tests), normal heart x-ray examination, continuous 24-hour two-channel ambulatory electrocardiograrn recording, M-mode dimensional and color Doppler echocardiography, and exercise stress testing. Based on an accurate neurological evaluation, including an electroencephalogram, the presence of any neurological disease was also excluded.


This case supports the hypothesis of involvement of the DA system in the migraine syndrome. The administration of apomorphine at a dosage which generally has no effect in normal subjects, was able to trigger in our patient dramatic nonpainful autonomic phenomena and hypotension, suggesting DA activation due to a hypersensitivity of DA receptors. The syncopal episode was conceivably due to a complete heart block induced by hypokinetic arrhythmia, in consideration of the premonitory symptoms. In fact, there was initially a short premonitory phase characterized by nausea, perspiration, yawning, epigastric distress, hyperpnea, and weakness. Hypokinetic arrhythmia could be explained by the in hibitory action of apomorphine on the sympathetic nervous system. Such an effect could be the result of stimulation of DA 2 receptors localized on autonomic ganglia and postganglionic nerve endings inhibiting norepinephrine release. Apomorphine is known to potentiate vagal bradycardia in the dog through stimulation of DA, presynaptic receptors located on vagal nerve endings. In our patient, the cardioinhibitory syncope was conceivably due to bradycardia, sinus arrest, atrioventricular block, a combination of these disturbances, or even asystole alone.

All such mechanisms may depend on activation of hypersensitive DA 2 receptors, which reduces the responses of the heart by inhibiting norepinephrine release from sympathetic nerve terminals. In conclusion, this report suggests two considerations: a reevaluation of hypersensitivity of DA 2 receptors, at least in some groups of migraine patients, and more concern about the potential cardiac effects of apomorphine'5 considering the widespread use of this drug in different conditions.

  • 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