Migraine is primarily a genetic illness, creating a "headache milieu" in the brain. In familial hemipletic migraine, the locus was found on chromosome 19p13. Gene therapy may eventually be utilized for migraine.
During the aura of migraine, there is a decrease in cerebral blood flow, spreading across the cortex at 2 to 3 mm/min. This oligemia begins occipitally and does not respect vascular territories, rendering vasoconstriction an unlikely explanation. Actual ischemia rarely, if ever, occurs. The oligemia may also occur in migraine without aura. The aura is primarily a neuronal phenomenon. One theory states that low brain magnesium, identified in migraine with aura, may increase N-methyl-D-aspartate (NMDA) receptor activity, leading to the aura phase. It is remarkable in migraineurs how much depression of cortical activity can occur without being evident clinically.
Neurogenic inflammation is important in the generation of the migraine pain. Calcitonin gene-related peptide (CRGP) is one of the main neuropeptides involved in the inflammation. Other peptides that may be involved include neurokinin A, vasoactive intestinal polypeptide and substance P. Plasma proteins leak into the dura mater as a result of the neurogenic inflammation. Triptans or dihydroergotamine (DHE) prevent the leakage of certain of these proteins. The blood-brain barrier is probably not functioning normally during migraine; this may allow drugs better access to the brain. Venous CGRP is elevated during migraine (and cluster), and may serve as a useful migraine marker.
The brainstem is most likely crucial in activating the migraine pain. Long-duration migraine, or recurrence of migraine, may involve continuous activation of the brainstem. The aminergic nuclei in the brainstem play some role in migraine. When the locus ceruleus (the primary noradrenalin nucleus) is stimulated, blood-brain barrier permeability and blood flow are affected. It is in these brainstem nuclei that certain drugs, such as antidepressants, may have their effect on migraine.
The trigeminal nerve, plus the upper dorsal cervical roots carry the pain of headache. The trigeminal nucleus caudalis, plus its extension into the high cervical cord, carries the pain produced by structures surrounding the brain. From the trigeminal nucleus caudalis, the pain information travels to the thalamus via the quintothalamic tract. From the thalamus, various projections proceed to the cortex.
A functional lack of serotonin at certain receptor sites is one element in migraine. Of the five known serotonin receptor classes, 5-hydroxytryptamine (5HT)1, and 5HT2 are the most important. The triptans and DHE are agonists at 5HT1, while methysergide is functional at 5HT2. 5HT1B is an inhibitory receptor at the trigeminal ganglion, extracerebral cranial vessels, and coronary vessels. 5HT1D is must less active at the coronary vessels. 5HT1D is much less active at the coronary vessels. Thus, newer drugs will ideally be more selective for 5HT1D than at 5HT1B. They would, ideally, work primarily at the brainstem level. The increased brainstem activity of 5HT1B and 5HT1D receptors lead to a marked decrease in neurogenic inflammation. The other 5HT-1 receptors (A,B,F) may have a role as well.
Aminobutyric acid (GABA) agonists such as valproate (Depakote), are important in the prevention of migraine. There is a relative hypersensitivity of dopamine during migraine. Medications that decrease dopamine such as the phenothiazines, may have an adjunctive role in migraine treatment. The important role of dopamine is currently a hot topic of research. Substance P antagonists and neurosteroids may or may not be helpful in headache therapy; several are currently being tested with relatively poor results thus far. The roles of nitrous oxide and NMDA are currently under investigation.