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Although there
is some understanding of the mechanism of migraine, its precise
underlying causes are unknown. Extensive reviews and volumes have been
published on the pathophysiology of headache and, in particular,
migraine.{12-15} It was primarily through the work of Wolff and colleagues{15} that vascular phenomenon were recognized as a mechanism responsible for the headache of migraine. Research to date suggests that the initiation of a migraine attack is a primary neuronal phenomenon with subsequent hemodynamic consequences.{16-18} Wolff divided the migraine attack into four phases: pre-headache, headache, late headache, and post-headache. The pre-headache phase is characterized by the constriction of certain blood vessels that supply the brain. Then, the beginning of the headache phase is characterized by vascular dilatation, particularly involving branches of the external carotid, such as the temporal, occipital, and middle meningeal arteries. Local tenderness of the scalp ensues, and the scalp vessels may become rigid. The nature of the headache then changes from a pulsatile type to a more constant dull ache. Alleviation of the early headache phase with vasoconstrictors (e.g., ergotamine) is cited as evidence that this pain is related to vasodilatation. In their most simplistic form these concepts can be reduced to the idea that the cerebral symptomatology, including the auras of classic migraine, is due to cerebral ischemia secondary to intracranial vessel spasm, and the ensuing headache phase is initiated by vasodilatation. However, vasodilatation may occur without pain, and additional factors are involved in the production of the headache. Local tissue changes take place (e.g., vessel edema, scalp swelling, and conjunctival chemosis) which may continue after vasodilatation has ceased. A wide variety of substances have causative roles in the production of large and small vessel dilatation as well as local tissue changes. Among the substances most frequently considered are the kinins (neurokinin and bradykinin), acetylcholine, histamine, serotonin, and reserpine. Sicuteri et al19 hypothesized that the following sequence occurs: the initial event is a local release of catecholamines (with vasoconstriction and increased urinary excretion of vanillylmandelic acid); during subsequent reactive hyperemia serotonin is released (documented by plasma serotonin decrease{20} and increased urinary 5-hydroxy indoleacetic acid{21}), presumably from platelets or mast cells, which sensitizes cranial pain receptors perhaps also affected by the kinins. Additional evidence suggests that there are nervous system connections between the trigeminal ganglia and cerebral blood vessels, termed the trigeminovascular system.{22} Trigeminovascular neurons and their peripheral unmyelinated nerve fibers contain the neurotransmitter peptide, substance P. Stimulation of this system by a variety of mechanisms would cause the release of substance P, which is postulated to increase vascular permeability and dilate cerebral blood vessels. The role of this system in the generation of human vascular headache may account for the effects of hormones or other circulating substances that change the receptive field properties of trigeminal ganglion cells. Individuals prone to chemically induced headaches from ingestion of tyramine, alcohol, phenylethyamine, monosodium glutamate, nitroglycerine, wine or chocolate also experience spontaneous headaches.{23} Extensive studies of the reactivity of blood vessels in migraine{24} and cerebral blood flow{17,18,25,26} suggest that abnormal vasomotor responses may be present in migraine patients between, as well as during, migraine attacks. There are several lines of indirect evidence that suggest a relationship between serotonin and migraine, making the understanding of the pharmacology of serotonin very important for understanding the pharmacology of the new serotonin agonist in migraine therapy.{9} The serotonin or 5-HT receptors consist of at least three distinct types of molecular structures: guanine nucleotide G protein-coupled receptors, ligand-gated ion channels and transporters. At least five 5-HT1 receptor subtypes are present in humans. Headaches bearing resemblance to migraine can be triggered by serotonergic drugs such as reserpine (a 5-HT releaser and depleter) and m-chlorophenylpiperazine (a serotonin agonist).{27,28} Other metabolic and endocrine factors also influence migraine attacks. According to Friedman and Merritt, 29 80% of pregnant women who are subject to migraine either lose their headaches or enjoy improvement. Callaghan,{30} however, found an increase in the severity of migraine in pregnancy. The use of oral contraceptives appears to increase the incidence and severity of migraine.{31,32} Whitty{33} felt that migraine might be precipitated by withdrawal of progesterone, while Somerville{34} found from a study of three women with regular menstrual migraine that their attacks were related to estradiol withdrawal rather than to falling levels of progesterone. Tyramine has also been invoked as a precipitating factor, especially in the so-called allergic migraine;{35} however, only approximately 5% of migraine subjects notice headaches precipitated by food. Some patients, however, are unusually sensitive to chocolate or alcohol, particularly red wines. Recent therapeutic trials with dietary therapy designed to avoid hypoglycemia suggest that glucose and/or insulin metabolism may play a role in the generation of vascular headache. The role of trauma in the production or exacerbation of a pre-existing migrainous tendency is still incompletely defined. Many individuals experience vascular headaches of the common migraine type following even minor head trauma.{36} A previously well controlled migraineur can experience a recrudescence of prior symptomatology following a head trauma. Such exacerbations are usually short-lived with a return to the pre-injury status in weeks to a few months. However, there are some patients who experience post-traumatic migraine headaches for years following a head injury. Other triggering events preceeding migraine attacks include bright light, especially sunlight reflected from water, exercise or exertion, and high altitude. Vascular headache of the migraine type may also follow orgasm.{37} The role of stress is less clear. It appears more likely that migraine headache follows a period of psychological stress than occurring during the time of stress. The pathophysiology of the migraine aura itself also has been extensively studied. Wolff showed that the use of a potent vasodilator, amylnitrate, could abort the migraine scotoma, (Fig 1): 
supporting the vasoconstrictor hypothesis. Milner{38} suggested that the scotomas of migraine and the neurophysiologic phenomenon, spreading depression of Leaġ, may be related. The spreading depression progresses across the cortex at approximately 3 mm/min, similar to the slow evolution of the visual phenomenon which had been detailed by Lashley{39}, and estimated to spread over the occipital cortex at a rate of 3 mm/min. Unfortunately, the concept of spreading depression cannot explain much of the symptomatology in migraine. The rate of spread of the visual phenomena is not always consistent with a uniform spread of 3 mm/min over the occipital cortex. Many patients experience just a "glare", and some have a continuously migrating visual form. The visual experiences in "retinal migraine" (see below), which are strictly monocular, cannot be readily explained by the occipital cortex changes. No clearly analogous "spreading depression" is apparent in the retina, which is quite different from the cerebral cortex in terms of functional anatomy, biochemistry, and information processing. Wilkinson and Blau{40} observed that the spreading depression of Leaġ has not been encountered in man or monkey by a variety of neurosurgeons and experts in cerebral blood flow. Raskin{14} discusses "spreading depression" further indicating that the hypothesis of "spreading depression" has many problems with it, but nonetheless it has focused interest on neuronal rather than vascular, pathogenetic possibilities. In short, factors more complex than spreading depression must be invoked to explain most of what is observed in migraine. One current theory is that all events are initiated by a "neuronal trigger" in the brainstem. A network of neural fibers emanate from the brainstem in the trigeminal vascular system supplying all the cerebral and meningeal blood vessels. The periodicity of migraine and the triggers that exist in some migraineurs remain unexplained. The fact that anticonvulsant such as Depakote and Topamax work as preventive agents supports the concept of a common central neural mechanism.
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