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- 31 janvier
2002
- Clinical
Neuropharmacology
- 1991;14(1):91-95
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- Apomorphine-induced
yawning in migraine patients: enhanced
responsiviness
- O
Blin, JP Azulay, G Masson, G Aubrespy, G
Serratrice
- Clinical Pharmacology &
CPCET, CHU Timone, 13385 Marseille
Cedex5
- The
neuropharmacology of yawning Argiolas A,
Melis
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Evidence from different experimental
models support the existence of peripheral
dopaminergic hypersensitivity in migraine
patients. These patients have an enhanced
reaction to dopaminergic agonists. A similar
hypersensitivity has been found in venous
vascular smooth muscle. Direct dopaminergic
agonists (e.g. bromocriptine and lisuride)
induce hypotension and nausea more frequently
and more intensely in migraine patients than in
controls (3,4). Piribedil infusion in migraine
patients increases the cerebral blood flow, and
causes nausea, vomiting, and a rapid fall in
blood pressure. The so-called piribedil test may
be of utility in the diagnosis and assessment of
dopaminergic sensitivity in migraine patients.
However, this test is not well tolerated, and
patients often refuse repeated evaluations.
Apomorphine, a reference dopaminergic agonist,
induces yawning in healthy volunteers. This
effect is antagonized by typical and atypical
neuroleptics but not by domperidone, a
peripheral dopaminergic blocker. Thus,
apomorphine-induced yawning may be useful in the
evaluation of central dopaminergic pathways in
humans, as proposed for schizophrenia or
erectile impotence. The goal of the present
study was to assess the dopaminergic sensitivity
in migraine patients.
PATIENTS AND METHODS
The study was an age and sex matched,
controlled design trial. Nine migraine patients,
two males and seven females, aged 23-55 years
(mean of 39.6 years) participated in the study.
After clinical and electrocardiographic
examination, informed consent was obtained from
all patients after the nature of the study had
been fully explained. All study subjects
suffered from common migraine according to the
criteria of the Ad Hoc Committee on
Classification of Headache. The patients had
been without medication for at least 1 month and
free of a migraine attack for at least 7 days
prior to the study. Nine healthy, age- and
sex-matched volunteers were tested as controls,
under the same conditions. Apomorphine (5
µg/kg) was prepared immediately before the
experiment and administered subcutaneously by a
physician in 1-ml injections. The subjects, who
had fasted since dinner on the evening before
the experimental day, arrived at the laboratory
at 8:00 a.m. A 15-min baseline period was
observed before the injection. After apomorphine
injection, the subjects were left alone in a
room for 60 min and videotaped. Yawning, ie.,
involuntary opening of the mouth.followed by at
least one deep inhalation, was continuously
coumed by two independent observers viewing the
videotapes. The relationship between the
cumulative number of yawns in the two groups was
compared by regression analysis.
RESULTS
Increased lacrimation was observed in all
subjects. One migraine patient mentioned
particular sensitivity to light and noise. A
migrainous woman had nausea. Yawning was
induced in seven of nine migraine patients.
An average number of 11 ± 6.9 yawns for
each migraine patient was reported in the 60-min
period following the injection of apomorphine.
The average time interval (expressed by 1/time)
between the apomorphine injection and the first
yawn was 0.058 ± 0.02 min. In controls, the
average number of yawns was 4.33 ± 1.6 in
the 60 mn period following the injection of
apomorphine. The average time interval
(expressed by 1/time) between the apomorphine
injection and the first yawn was 0,066 ±
0.02 min. The cumulative number of yawns as a
function of time showed that the correlation was
statistically significant in migraine patients
(F = 27.12, df = 43, p < 0.01) and in
controls (F = 75.8, df = 43, p < 0.01).
Comparison of the regression graphs indicated a
significant difference between migraine patients
and controls (i = 3.08, p < 0.05). The mean
time between apornorphine injection and induced
yawning was not significantly different between
controls and migraine patients.
DISCUSSION
Yawning is a poorly documented physiological
behavior that is common in migraine patients.
Yawning accompanied by other psychic or physical
signs may be a prodrome of a migraine attack.
The central dopaminergic systems play a major
role in yawning. In animals, various studies
using D1 and D2 agonists and antagonists suggest
that yawning is linked to joint D1-D2 action. In
humans, yawning is modified in diseases related
to dopaminergic dysfunction, such as Parkinson's
or Huntington's disease. We have previously
demonstrated in placebo-controlled, double-blind
studies that low doses of apomorphine induce
yawning in healthy volunteers. We were unable to
demonstrate a dose-effect relationship in these
studies. Therefore, our migraine patients and
controls received only one dose in the present
study. Parkinsonian patients also yawn after
high doses of apomorphine. This findIng does not
necessarily reflect a hypersensitivity and
deserves further studies using low doses of
apomorphine.
The significant difference in the number of
apomorphine-induced yawns between migraine
patients and controls indicates enhanced
responsiveness of migraine patients to
apomorphine challenge. Although the occurrence
of complex behavioral modifications or sedation
may modify the yawning response, this result
favors a central dopaminergic hypersensitivity
in migraine patients. This hypersensitivity,
which we could demonstrate in our study, is
consistent and deserves two comments:
(a),Whether the symptoms of migraine headaches
are related to vascular or neural changes
remains controversial. The definite proof of
constant central dopaminergic hypersensitivity
in migraine patients would support the
hypothesis of the involvement of monoamines,
acting centrally as neurotransmitters, in the
underlying mechanisms of migraine. (b) In regard
to the treatment, dopamine receptor blockade by
domperidone prevents migraine in patients who
experience typical prodromes before the
headache. The domperidone effect is
dose-related. The piribedil test does not allow
one to predict the effectiveness of domperidone
in a given migrainous patient. By referring to
nausea and drop in blood pressure, the peribedil
test evaluates peripheral dopaminergic
sensitivity. Certain migraine prodromes (e.g.,
psychological changes) arerelated to central
modifications. The central dopaminergic
sensitivity evaluation, using apomorphine
induced yawning, may be useful in patients who
experience these symptoms.
Also, other neurotransmitter systems are
involved in yawning. The serotoninergic system
modulates dopaminergic agonist-induced yawning
and plays an important part in the etiology of
migraine. Apomorphine-induced yawning apparently
is more frequent in women than in men. This fact
may be related to the higher frequency of
migraine females and to the varying incidence of
migraine during the stages of the sexual life of
migraine fernales.
CONCLUSION
Apomorphine-induced yawning is a
well-tolerated test that may be of use in the
evaluation of central dopaminergic pathways.
After demonstrating the intertest variability,
this test could easily be reproduced in the
absence of a migraine attack (as donc here),
during an attack., or as the disease progresses
with or without treatment. Further studies using
a double-blind, placebo-controlled design are
required.
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