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.
[...]
DISCUSSION
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
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