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.
CASE HISTORY
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.
COMMENTS
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.
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