Induce Migraine Attacks Research Articles

Serotonin in migraine: theories, animal models and emerging therapies.

A role for serotonin in migraine has been supported by changes in circulating levels of serotonin and its metabolites during the phases of a migraine attack, along with the ability of serotonin-releasing agents to induce migraine-like symptoms. The development of serotonin receptor agonists with efficacy in the clinic for the alleviation of migraine pain further implicates serotonin as a key molecule in migraine. Several theories regarding the etiology of migraine have been proposed. The vasodilatory theory of migraine suggested that extracranial arterial dilation during an attack was related to migraine pain; a theory supported when vasoconstrictors such as sumatriptan alleviated migraine pain. The neurological theory of migraine proposed that migraine resulted from abnormal firing in brain neurons. Cortical spreading depression, one facet of the neurological theory, could explain the prodrome of migraine. The neurogenic dural inflammation theory of migraine supposed that the dural membrane surrounding the brain became inflamed and hypersensitive due to release of neuropeptides from primary sensory nerve terminals. Substance P, calcitonin gene related peptide and nitric oxide are all though to play a role in the dural inflammatory cascade. Animal models of migraine have been utilized to study the physiology of migraine and develop new pharmaceutical therapies. One model measures the shunting of blood to arteriovenous anastomoses based on a proposal that migraine primarily involves cranial arteriovenous vasodilation. Another model utilizes electrical stimulation of the trigeminal ganglion to induce neurogenic dural inflammation quantified by the resulting extravasation of proteins. Pharmacological agents such as meta-chlorophenylpiperazine (mCPP) and nitroglycerin have also been used to induce dural extravasation in animals. Both compounds also induce migraine attacks in individuals with a history of migraine. In addition, Fos, a protein produced by activation of the c-fos gene, has been measured as an index of migraine-like pain transmission to the CNS following chemical or electrical stimulation of the trigeminal nerve. A role for serotonin in migraine is further supported by the efficacy of serotonin receptor ligands. Sumatriptan is an agonist at 5-HT1D and 5-HT1B receptor subtypes, and effective in treating migraine pain and associated symptoms. Recently, selective 5-HT1F agonists have been proposed for the treatment of migraine, without the side effects associated with the present 5-HT1D and 5-HT1B receptor agonists. A role for 5-HT2B receptors has also been suggested the initiation of migraine, supporting use of selective 5-HT2B receptor antagonists in migraine. Thus, agents that modulate 5-HT1B, 5-HT1D, 5-HT1F and 5-HT2B receptors either have or may have clinical utility in the therapy of migraine headache.

Headache induced by serotonergic agonists--a key to the interpretation of migraine pathogenesis?

Serotonergic agonists such as m-chlorophenylpiperazine (m-CPP) and fenfluramine may induce migraine attacks. This has led to opposing theories concerning the role of 5-hydroxytryptamine (5HT) in triggering migraine attacks; is there hyperfunction or hypofunction of the central serotonergic system. Our review of the literature strongly suggests that m-CPP and fenfluramine provoke migraine attacks by stimulating, directly or indirectly, the 5HT2C/5HT2B receptors, although there is no total agreement with this interpretation. Central 5HT hypersensitivity in migraine patients, probably due to 5HT neuronal depletion, is proposed on the basis of review of electrophysiological tests and neuroendocrine challenge paradigms.

The autonomic nervous system and the regulation of arterial tone in migraine.

Abnormal regulation of the large cranial arteries seems to play a significant role in the mechanisms of migraine pain. Thus, vasodilatation of extra- and intracranial conductance arteries has been described both during spontaneous migraine attacks and during experimentally provoked vascular headaches. The regulation of the diameter of these arteries is complex and involves autonomic, trigeminovascular, endothelial and humoral mechanisms. Studies concerned with the function of the autonomic nervous system in migraine suggest that a mild parasympathetic dysfunction may be present. Cerebral arteries in migraineurs are hypersensitive to nitric oxide, which may induce migraine attacks. As the enzyme responsible for nitric oxide synthesis is present in parasympathetic nerve endings around cerebral arteries, this supports a role for the parasympathetic nervous system in migraine. In addition, vasoactive transmitters released from perivascular trigeminal nerve endings may be implicated. Several of these aspects are closely linked to the presumed mechanisms of action of modern migraine therapeutics.

Plasma vasopressin levels in induced migraine attacks.

Vasopressin (aVP) at low concentrations functions as an antidiuretic hormone and has vasoconstrictive effects. To investigate the possible role of aVP in the pathogenesis of migraine, six patients with a history of induced migraine were given 100 g chocolate, and blood samples for plasma aVP were taken before ingestion and every hour for 4 h. In one patient who presented with severe headache and nausea the base-line plasma aVP concentration was 15.2 pg/ml; it fell to 3.2 pg/ml at 2 h before rising to 10 pg/ml at 3 h and 4 h as the symptoms worsened. In the five patients with moderate or no headache plasma aVP concentrations remained in the normal range (less than 3 pg/ml) throughout. The results suggest that aVP does not have a role in the aetiology of migraine. The possibility exists that during severe attacks of nausea there is release of aVP, which may be responsible for the facial pallor, antidiuresis, and coagulation abnormalities occasionally observed in migraine.

Plasma Vasopressin Levels In Induced Migraine Attacks

Plasma Vasopressin Levels In Induced Migraine Attacks

Regulation of regional cerebral blood flow during and between migraine attacks.

Cerebrovascular reactivity to voluntary hyperventilation, moderate hypertension, and physiological activation was studied in nine patients during induced migraine attacks and in four patients between their attacks. Regional cerebral blood flow was measured by the xenon 133 injection technique in 254 areas of one hemisphere. The partly hypoperfused hemisphere allowed for comparison of adjacent hypoperfused and normally perfused brain areas. During attacks the carbon dioxide reactivity was decreased to 2.8 +/- 0.8% per mm Hg in the oligemic regions compared with 5.8 +/- 0.8% per mm Hg in the normally perfused brain. Blood pressure autoregulation was normal in all brain regions. Regional blood flow increase in response to physiological activation was severely impaired in the hypoperfused brain areas, whereas neighboring normally perfused regions reacted normally. Confinement of the regulation abnormalities to the area of the oligemia supports our suggestion that the blood flow changes are caused by a change in local metabolism. Between attacks of migraine, the patients had normal regulation of brain circulation.