As with other complex disorders, the etiology of migraine is not well understood. There are some conflicting ideas and a wide variety of opinions on the origins of the disorder. The disease is generally considered to be multifactorial in nature. It is the most common type of chronic headache pain and affects up to 24% of the female and 12% of the male population(1). Migraine does tend to run in families although family-, twin- and population based studies have suggested that inheritance is not the only factor contributing to the onset of migraine.
Migraine headaches are classified in one of two ways: migraine with aura or migraine without aura. About 1/3 of migraineurs (those afflicted by migraine headaches) experience transient focal neurological symptoms prior to the onset of a migraine. These symptoms are known collectively as aura. Aura is most commonly some type of visual disturbance such as flashing spots or enlarged blind spots. In some individuals the hearing may be affected. Less frequently, aura may include the perception of touch. Migraine pain starts 15-45 minutes after aura. Although the pain is probably comparable, there are physiological differences between individuals with migraine without aura (MWOA) and those with aura(MWA) (2,5).
Because there is no clear biochemical marker for migraine, diagnosis of the condition is based on clinical findings alone. However, migraine pain is difficult to miss. It normally includes intense throbbing pain localized in one side of the head, nausea, vomiting, and hypersensitivity to light, sound and/or smell. These symptoms last for a number of hours. At least one genetic marker for a migraine-associated disease has been identified(1). Mapping of the human genome has stimulated interest in finding a common migraine gene, if such a thing exists. At any rate, research will undoubtedly continue given the large number of people affected and thus the large potential to profit from the alleviation of pain.
Research on migraine pain can be categorized into one of three areas. First, there are studies on neuroexcitatory compounds themselves. There are also studies on various types of receptors specific for compounds expected to be involved in migraine and proteins also implicated in migraine. Finally, there are studies on ions, ion transport channel disorders (channelopathies), and phenomena that change ion concentrations such as cortical spreading depression. These three areas are not by any means independent of one another; however, they are convenient sections in which to consider the literature.
Some amino acids act as neurotransmitters or precursors to neurotransmitters. This is especially true for glutamate. Although it is necessary for brain metabolism, it can be excitotoxic at high levels. Aspartate is also known to be involved in neurotransmission. Both amino acids are implicated in epilepsy. Epileptic seizures, which can be thought of as electrical storms in the brain, cannot occur without excitotoxic neurotransmission. Cysteic acid [-O3S-CH2-CH(NH3+)COO-]and homocysteic acid are also known to be neuroexcitatory amino acid derivatives(2).
Interestingly, blood plasma levels of neurotransmitting amino acids in migraineurs are significantly different from controls. Migraine patients' amino acid levels were analyzed both during migraine attack and in between migraines. The patients were also categorized by whether or not they experienced aura. Cysteic acid, glutamic acid, homocysteic acid, glutamine and glycine levels were all elevated (with respect to negative controls) in patients with both types of migraine during the "normal" time between attacks. Tryptophan levels were elevated only in MWOA patients. It may be noted that tryptophan is a precursor to serotonin, an important neurotransmitter. During migraine, total plasma thiols(cysteine and cystine), cysteic acid, glutamic acid, homocysteic acid, glutamine, glycine and tryptophan were all found to be high. Non-neurotransmitter amino acid levels of migraineurs were always statistically indistinguishable from the control group.
The link between migraine and specific receptors has often been suggested(2-7). Many pharmacological studies have been conducted to determine whether the blocking of specific receptors is effective in treatment of migraine(3,5,6). Some of the drugs known to have some level of effectiveness include opioids, ergots, triptans and valproate. These work at different receptors. Pharmocological studies seem to be directed more at results than clearly understanding the mechanism of interaction of the drug with the receptors. One of the more common receptors mentioned in the literature are those of the 5-HT variety or serotonin (5-hydroxytryptamine) receptors(2,3,6). Triptans have high affinity for the 5-HT1 receptor. 5-HT1 serotonin receptors are highly expressed in the trigeminal nerve vascular region. The trigeminal nerve is known to become activated during migraine. The triptans are effective antimigraine agents for some patients but not for all. The serotonin precursor tryptophan was found to be elevated only in patients with MWOA; it would be interesting to determine whether these were the patients with no response to tryptan(3,2).
Familial hemiplegic migraine (FHM) is a rare genetic channelopathy characterized by mutations in the CACNA1A gene (1). This particular gene codes for the brain-specific P/Q type calcium channel alpha1 subunit. These calcium channels are voltage gated channels that occur in neurons. These channels open with the nerve signal wave of depolarization and allow the influx of Ca+2. The CACNA1A gene is located on chromosome 19 at p arm region13. The disorder is inherited as an autosomal dominant trait and is characterized by transient hemiplegia (partial paralysis) during the aura prior to onset of the migraine.
One pharamcological study proposed that the pain of migraine comes from neurogenic vasodilation of meningeal blood vessels. This may result from the activation of the trigeminal nerve. Plasma levels of the potent vasodilator calcitonin gene-related peptide (CGRP) are elevated during headache. The study suggests that CGRP receptor antagonists may be the key to blocking migraine pain(3).
Migraine is a neurological disorder. Given the tight association between ions and neurological tissue, ion fluxes are relevant to neurological disorders. A dramatic change in ion distribution underlies the phenomenon of cortical spreading depression (CSD). CSD has been linked with aura and migraine through several means. Magnetic brain imaging studies in people with migraine pain showed three distinctive patterns: large amplitude waves, slow field changes and suppressed spontaneous cortical activity. The same patterns were recorded in anaesthetized animals with induced CSD. It has been suggested that aura begins with the start of CSD and that migraine pain does not start until the spreading depression wave reaches the pain receptors. This would be consistent with the time delay experienced between aura and migraine pain.
CSD is a propagating wave front of depolarized neurological cells. CSD can be instigated at some point by raising the tissue susceptibility; hypoglycemia, hypoxia, increasing [K+], decreasing [NaCl], mechanical, chemical, and electrical stimulation all make brain tissue more susceptible to CSD. The wave of depolarization originates at some central position and moves outward in all directions at a rate of 2-3 mm/min. The neuronal bioelectric activity is depressed with the wave. Cellular ion distributions undergo dramatic changes; K+ and H+ leave the cell whereas Na+, Ca+2 and Cl- enter with water. The extracellular bioelectric potential becomes negative with an amplitude of 10-30 mV and stays negative for up to a minute. There may be a sudden upsurge in potential following the wave. The cells eventually repolarize and potential readings return to normal levels. Interestingly, CSD is accompanied by increased glucose utilization and oxygen consumption. The phenomenon is known to be associated with epilepsy and epileptic seizures. In fact, many of the drugs used to treat epileptic convulsions are effective in treating migraine. Similarly, some antimigraine drugs increase the epilepsy threshold(7). CSD has repeatedly been shown to affect the regional cerebral blood flow. A moderate but prolonged decrease in blood flow during CSD is terminated with a brief dilation of arterioles at the time of cellular repolarization(2,4,7).
Calcium ions have been put forth as important in the role of migraine, however, calcium dynamics are not well understood in relation to migraine. There is some suggestion that calcium dynamics play a paradoxical role in both instigating and preventing CSD. Ca+2 channel blockers such as flunarizine and nimodipine have been found to prevent migraine attacks after months of treatment. Other Ca+2 channel blockers such as NiCl2 and amiloride seemed to condition the tissue and cause CSD. The authors conclude that more study is necessary to clarify the dose-response relationship between calcium channel blockers and eliciting of CSD in human tissue(4). Regardless of the calcium relationship, CSD does seem to be the most upstream event known to be associated with migraine.
Migraine is a phenomenally complex disorder. The fact that so many papers are published on so many different topics touted as important to migraine implies that this condition is expressed in many ways. The genetics explanation for migraine is supported by the elevated levels of neuroexcitatory amino acids in migraineurs. Since these elevated levels persist even between migraines when patients appear normal, these people may in fact be metastable with a high endogenous CNS excitability(2). Outside factors including stress could have more of an effect when levels of neuroexcitatory compounds are naturally elevated. This condition of having a biochemistry significantly different from controls suggests some genetics or expression problem, but the family and twin studies show that more is at work than just genes(1).
Looking at migraine from the symptomatic side seems to suggest that CSD is the most fundamental event in the migraine disorder. The primary instigator for the spreading depression which seems to occur spontaneously in migraineurs' brains is unknown. Understanding of this event may one day allow for prevention of the problem that leads to so much pain in the first place. Targeting pain receptors with various drugs may offer some relief, but eliminating the source of the pain may be a better solution.
Copyright © 2002 Beth Reed and Koni Stone
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