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mise à jour
31 janvier 2002
Clinical Neuropharmacology
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
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.


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.


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.


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.


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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