Migraine frequently runs in families suggesting that hereditary factors are clearly  involved.^{20, 21}  Familial hemiplegic migraine, a rare subtype of migraine, is inherited as an autosomal dominant pattern  or with sporadic inheritance.  Familial hemiplegic migraine is caused by mutations in specific genes.  The first gene identified was the CACNA1A gene located on the chromosome 19p13 which coded for the pore-forming subunit Cav2.1 of P/Q-type sodium channels.  This gene is found in approximately 75% of such findings.  This would define this type of migraine as a channelopathy.  It has also been suggested that migraine with aura has a loci on chromosome 4Q.²²

It was primarily through the work of Wolff and colleagues¹⁵ 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 primarily a neuronal phenomenon with secondary hemodynamic consequences.^17,23-26  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. 

  Migraine, then, may result from dysfunction of brain-stem or diencephalic nuclei involved in nocieceptive modulation of afference from the trigeminal vascular system.¹⁶  Positron-emission tomography has detected activation in the brain-stem during attacks of migraine.^27,28 

Sicuteri et al²⁹ 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 decrease³⁰ and increased urinary 5‑hydroxy indoleacetic acid ^31),  ), 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.  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.³³  Extensive studies of the reactivity of blood vessels in migraine³⁴ and cerebral blood flow^24,25,35,36 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 such as reserpine (a 5-HT releaser and depleter) and m-chlorophenylpiperazine (a serotonin agonist).^37,38

Other metabolic and endocrine factors also influence migraine attacks. According to Friedman and Merritt,³⁹ 80% of pregnant women who are subject to migraine either lose their headaches or enjoy improvement.  Callaghan,⁴⁰ 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.^41,42  Whitty⁴³ felt that migraine might be precipitated by withdrawal of progesterone, while Somerville⁴⁴ 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;⁴⁵ 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 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. Milner⁴⁸ suggested that the scotomas of migraine and the neurophysiologic phenomenon, spreading depression of Leao, 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 Lashley⁴⁹, and estimated to spread over the occipital cortex at a rate of 3 mm/min.  

It is currently believed that the aura of migraine may be the human counterpart of the animal phenomenon of Leão’s spreading depression.⁵⁰ The aura is characterized by a wave of decreased bloodflow or oligemia pasing across the cortex^{24, 51-53} at a slow rate (2 to 6 mm per minute) consistent with the threat of visual phenomenon through the visual cortex, as mentioned above.⁵⁴ There is a short phase of hyperemia preceding the oligemia which may be a correlate of the scintillating scatoma, also a characteristic of migraine with aura.⁵⁵   However, persistent oligemia is probably a response to depressed neuronal function and is present when the headache starts, as noted by Goadsby.^16,53,56  Such findings coupled with the direct evidence of adequate local oxygen supply⁵⁷ vitiate the theory that migraine is just a vascular headache.¹⁶

Three cardinal factors are important in the pathogenesis of migraine, according to Goadsby.¹⁶  These include the cranial blood vessels, the trigeminal innervation of these vessels, and the reflex connection of the trigeminal system with a cranial parasympathetic outflow.  The pain sensitive structures within the cranium, such as large blood vessels or the duramator, are innervated by branches of the ophthalmic division of the trigeminal nerve⁵⁸  and the posterior fossa structures are innervated by branches of C2 nerve roots.⁵⁹  As indicated by Goadsby,¹⁶ involvement of the ophthalmic division of the trigeminal nerve and the overlap with structures innervated by C2 explain the common distribution of the pain of migraine in the frontal and temporal regions, as well as involvement of parietal occipital and high cervical regions, by referred pain.  Peripherally, the trigeminal afference are activated in migraine by the release of calcitonin gene-related peptide (CGRP) a vasodilator⁶⁰ and, while the mechanism of pain generation is not entirely clear, animal studies suggest that pain is caused by a sterile neurogenic inflammation in the dura mater.⁶¹  This may, in part, explain the prevention of migraine pain by substances such as botulinum toxin Type A which inhibit the release of CGRP.⁶²  As stated by Goadsby,¹⁶the pain may be a combination of an altered perception—as a result of peripheral or central sensitization – of craniovascular input that is not usually painful⁶³ and the activation of feed-forward neurovascular dialator mechanism that is functioning specific to the first “ophthalmic division of the trigeminal nerve.”⁶⁴ Again, the effect of botulinum toxin Type A in reducing migraine pain may interfere with this peripheral activation and, therefore, function to provide peripheral desensitization.⁶²

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