What Is A Migraine Biology Essay

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As wrongly believed by many, a migraine is not simply a headache. Recent studies have shown that a migraine is a genetic neurological disease. One of the many symptoms is headaches, usually on a single side of the head. This headache is sometimes quickly accompanied by nausea and vomiting, and an amplified sensitivity to bright lights and noise, along with exhaustion and diarrhoea. Genetic factors have some significance in the physiological processes of migraine by lowering the trigger threshold for migraine attacks. The majority of genetic research of migraines has mainly been focused on the identification of genes involved in familial hemiplegic migraine (FHM). This type of migraine is a rather rare subtype of migraine with aura.

Types of migraine

Migraines can be classified into two main categories; common migraines and classic migraines. A common migraine, as the name suggests, is found in patients far more frequently than the classic migraine. Common migraines have a higher average attack frequency and are usually more disabling than classic migraines. A common migraine is one that has no aura, whereas a classic migraine is one that does have an aura. An aura is a combination of neurological symptoms and usually occurs just before the migraine begins. Auras are more commonly visual but can also be sensory and motor. Visual auras can include flashing lights and zig zag figure near the point of fixation that may gradually spread from right to left or vice versa and assume a laterally convex shape with an angulated sparkling edge leaving variable degrees of loss or impairment of visual acuity surrounded by fields of normal vision. The next most common auras are sensory disturbances in the form of parethesias (pins and needles) slowly moving from the point where it originated and affecting a greater or smaller part of one side of the body and face. Numbness may also occur in its wake, but numbness may also be the only symptom [1] . There may also be some fully reversible speech impairment, but this is generally quite rare. Migraines associated with motor auras are called hemiplegic migraines and may occur on a hereditary basis within families and an infrequent basis among individuals [2] . The auras generally run in the order in which I have described them although other orders are possible.

Phases of migraine

Generally they both last between 4 - 72 hours. In approximately 30% of patients, the migraine is preceded by premonitory symptoms, which collectively are sometimes referred to as the prodrome phase. There may be a combination of one or more of the following five phases:




resolution [3] 


All five of these phases do not necessarily need to occur for an attack to be classed as a migraine. The prodromal and aura phases do not always take place, and the patient may not even suffer from a headache after having an aura, however this is rarely the case. This is called the silent migraine and more often occurs later in life, and more often in men than in women [4] .

In the prodromal phase, the patient can become easily irritated, fatigued, have muscle stiffness, depression, general mood alterations and many other symptoms. These symptoms can come about anytime in the preceding hours or days before the headache. This phase is also sometimes referred to as the premonition phase as after it first happens, the patient can tell when they are about to have an attack and try to prepare for it.

In the headache phase, as stated before, the attack takes place normally on one side of the head and the pain can be exacerbated by bright lights and noise, due to over-sensitization, which is also accompanied by nausea. The fourth stage is resolution, which involves a reduction in pain, but can be replaced by fatigue and irritability [5] . The postdrome stage lasts for a period of time after the headache where the migraine sufferers may be irritable and fatigued. They may have difficulty concentrating, experience limited food tolerance, mood changes and the scalp may also be tender.

Possible causes of migraine - fig 1

The exact cause of migraine is still undetermined, however there are many theories surrounding the issue. I will now discuss the most common perception and the unifying theory as to the cause of migraines.

An older, but most common explanation for migraines revolves around serotonin, a very important neurotransmitter. The release of serotonin causes vasoconstriction, which in turn lowers the pain threshold. In reaction to this, nerves surrounding the blood vessels respond by releasing chemicals that induce inflammation so there is vasodilatation of the blood vessels and it is this which directly causes the pain. Before a migraine attack, serotonin levels have been detected to be unusually high in the brain, whereas during the actual migraine attack they have been recorded as being extremely low. Low levels of serotonin cause the blood vessels to be abnormally large [6] i.e. the vasodilatation. The immediate area around the expanded blood vessels becomes inflamed and irritates the nerve endings causing pain due to the electrochemical imbalance.

A more recent form of this argument proposes that the visual auras are caused by changes in blood flow patterns in the brain and cortical spreading depression (CSD)3, which refers to a wave of intense neuronal activity that slowly progresses over the cortex and is followed by a period of neuronal inactivity [7] . The similar propagation velocity of CSD and visual scotoma during migraine aura led to the assumption that CSD could be the underlying mechanism of migraine aura [8] . Even though there is a large difference in brain size and complexity between humans and animals such as rats [9] , trigeminal innervations appear to be extremely similar. The trigeminal nerve conveys sensory information to the face and a large proportion of the head. From experiments on animals, but not yet in humans, it is suggested that the CSD activates trigeminovascular afferents and evokes a series of cortical meningeal and brainstem events consistent with the development of headache [10] . CSD therefore precedes plasma protein leakage within the dura mater, which is recognized by pain receptors in the blood vessels of surrounding tissues causing a throbbing unilateral pain. The release of vasoactive peptides from trigeminal sensitive endings, which supply cerebral circulation, due to the activation of the trigeminovascular system are considered to be the final pathway which mediates migraine attacks [11] .

Types of familial hemiplegic migraine

FHM type 1 (FHM-1) is caused by a mutation in the CACNA1A gene and that encodes the pore-forming [alpha]1A subunit of voltage-gated neuronal P/Q-type Ca2+ channels (Cav2.1 Ca2+) [12] .Through experiments on mice carrying the human R192Q gene, pure FHM-1 mutation reveal a gain in function at multiple levels:

Pure gain-of-function effect on Ca2+ channel current,

Enhanced neurotransmission at the neuromuscular junction

Reduced threshold and increased velocity of CSD [13] 

Another mutation (S218L) in the same gene alters calcium channel activation by making the voltage needed to reach threshold much more negative, thus allowing more hyperpolarizing voltages to be able to open the channels. Minor head trauma can cause severe and prolonged auras in patient that carry the S218L mutation. The "gain in function" results in increased Ca2+ influx, which can potentially lead to increased neurotransmission.

FHM type 2 (FHM-2) mutations in the ATP1A2 gene that encodes effect mainly the Na+/K+-ATPase pump, located mainly in glial cells [14] . They pump of sodium out and potassium into the cells, which provides a steep sodium gradient essential for the transport of calcium and certain amino acids. Mutations in this gene tend to cause a "loss of function" meaning decreased pump activity. This causes reduced uptake of ions and neurotransmitter as well as slow clearance of potassium and glutamate, which leads to an increased susceptibility to CSD.

The third subtype of FHM (FHM-3) is caused by a mutation in the SCN1A gene which encodes a voltage-gated sodium channel [15] . This mutation causes a much faster recovery from sodium-channel inactivation than normal after depolarization. This results in persistent sodium influx into the neuron leading to neuronal hyper-excitability. It has been suggested that due to its importance in the propagation of action potentials, that this recovery rate may assist repetitive high-frequency neuronal firing and enhanced neuronal excitability as well as an increased neurotransmitter release.

Based on some studies, it can be conceived that increased susceptibility to FHM may occur due to a disturbed ionic balance as well as an increased release of the excitatory neurotransmitter glutamate [16] . In all of the above types of mutation, the final outcome leads to mechanisms that support the hyper-excitability theory of the sufferer's brain.

Triggers of migraine

Migraines do not tend to occur randomly but seem to have certain triggers. These triggers are a number of factors which help with initiation of the migraine, but are not the specific cause. There are many common triggers; however they do vary from patient to patient.

Dietary triggers - For example;

Beverages/alcohol, chocolate, cereals, dairy products (aged cheese), meats/poultry, fish, vegetables etc.

Certain foods may contain chemical amines, similar to serotonin which constricts the blood vessels causing a reaction vasodilatation, which in turn leads to pain. However it was found that alcohol, caffeine withdrawal, and missing meals are the most important dietary factors that trigger migraine [17] . Daily consumption of caffeine can be harmful in the sense that its withdrawal can lead to rebound headaches. Caffeine is also used in conjunction with some over-the-counter (OTC) medicine (including anti-migraine medicine) as it amplifies the medicines analgesic effect. Thus caffeine consumptions can interfere with the anti-migraine drugs.

Environmental triggers

Sights - bright lights/glare

Sounds - loud noises

Smells - strong odours

Weather - change in climate, humidity, wind levels.

If there is a dramatic change in environment, some people become more susceptible to migraine attacks. Travelling to places with higher altitude than normal or going diving can lead to increased sensitivity to migraines. Even general changes to their lifestyle that involve adaptation such as switching jobs can have the same effect.

Emotional triggers

Anger, Anticipation, Anxiety, Depression, Excitement, Fatigue, Stress

Above are just a few emotional triggers for migraine. Stress is one of the most common emotional triggers, day-to-day stress of trying to handle difficult situations being the most reported trigger. In a study, migraine patients were found to have elevated plasma cortisol levels, an indicator for stress, during attacks compared to the inter-ictal phase [18] . Repressed emotions such as anxiety, excitement and fatigue can increase muscle tension which can intensify the severity of migraine.

Physiological triggers

Lack of exercise, eyestrain, fasting or missing a meal, fatigue, lack of sleep, motion, oversleeping.

Disturbances such as sleep deprivation, too much sleep, and frequent awakening at night are associated with migraines, whereas improved sleep habits have been shown to reduce the frequency of migraine headaches. Sleep also has been reported to shorten the duration of migraine headaches.

Hormonal triggers



hormone supplements

Over a quarter of the female population experience migraine at some time in their lives and more than half of these women report a link between migraine and menstruation [19] . Menstrual migraine is a widespread condition that is associated with significant disability. Oestrogen has powerful effects on the serotonergic system, increasing serotonergic tone. It also facilitates the glutaminergic system, potentially enhancing neural excitability [20] .

Treatment of Migraine

Once a patient has been diagnosed with migraine and any other additional patient disorders (comorbidities) have been noted, a treatment plan must be made for the patient. This must me done separately for each patient as each case of migraine is likely to be very different due to all the possible triggers and so forth. The patient must be told about the illness and how to keep it under control. For example, the triggers should be discussed and how to avoid them by making changes in their lifestyle, behavioral changes, sometimes physical techniques i.e. exercise and finally, prophylactic and abortive treatments.

Treatment of migraines is fought mainly on two fronts; preventing attacks from happening and trying to ease the symptoms caused when an attack does in fact take place. The other method of treatment is by avoiding some of the triggers discussed earlier. Sufferers are sometimes told to keep a record of the regular occurrences in the days/hours leading up to a migraine attack so that triggers common to that patient can be avoided in future so as to lessen the frequency of the migraine attacks.

Prophylactic (preventative) treatment)

Preventative medications are given to patients who have regular migraine attacks. The level of frequency of migraine to be seen as occurring regular enough to be prescribed these medications depends entirely on the physician. These preventative medications must be taken on a daily basis, regardless of whether a migraine takes place. When there is only a partial response from taking one drug, one or more drugs can be taken in conjunction with the first drug. Also if one drugs' dosage cannot be increased due to a build up of intolerance or if maximal dosage has been reached, then it is common for another drug to be taken with to first.

Preventative treatment types


Anti-depressants are often used in the treatment of migraines because depression is believed to be caused by an irregularity in serotonin transmitter systems. This causes a deficiency, which means that increased concentrations of serotonin at the receptor should ease to an extent the symptoms of depression and thus have a similar effect on migraines.

The tricyclic antidepressants (TCAs) are commonly used for migraine prophylaxis. Agents (MAOIs) that increase the levels of serotonin by inhibiting their metabolism and drugs that increase these levels at the receptors by inhibiting the uptake of 5-HT are involved.

Similarly, selective serotonin reuptake inhibitors (SSRIs (e.g. fluoxetine)) increase serotonin levels by inhibiting the reuptake of serotonin after being released in synapses. They have also been proven to promote neurogenisis in rats [21] .

Gabapentin - The effect of gabapentin is to increase GABA concentrations in the brain. This may provide a possible explanation for its mechanism of action in migraine prophylaxis. Increases in GABA may suppress the unusual cortical activities that inspire migraine with aura and reduce central neuronal hyperexcitability [22] .

Anti-convulsant agents

Topiramate - A relatively new, anticonvulsant drug. Although it's exact mechanism of action is not known, scientific studies suggest that It can influence the activity of some types of voltage-activated Na+ and Ca++ channels, GABAA receptors and the aamino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate subtype of glutamate receptors [23] . It exerts its effects via through protein phosphorylation, which has lead to the hypothesis that TPM may bind to the membrane channel complexes and modulate the ionic conductance through the channels [24] .

ß-Receptor blockers e.g propranolol

These drugs work by reducing blood pressure and through other central nervous system and vascular effects, the mechanisms of which are not yet fully understood.

Calcium channel blockers - these generally work by preventing the constriction of blood vessels that occurs during the initial phases of migraine attacks.

Botulinum toxin - recently, it was found to have antinociceptive effects that are thought to be independent of its normal muscle-relaxant action. Clinical trials support the efficacy of BTX type A (and possibly also type B) in the treatment of migraine. [25] 

Abortive treatment

Once the migraine attack has begun, there are two methods of reducing the pain: with and without drugs. Many medications have been used for acute treatment of migraines such as; analgesics, antiemetics, anxiolytics, nonsteroidal anti-inflammatory drugs, ergots, steroids, major tranquilizers and narcotics. Recently, triptans (selective 5-HTlB/D (serotonin) agonists) have been used with success (e.g. sumatriptan, rizatriptan, zolmitriptan and naratriptan) [26] .

Non-steroidal anti-inflammatory drug (NSAIDs)

These are considered the first line of treatment for mild-moderate migraines. NSAIDs relieve pain by inhibiting prostaglandins, compounds implicated in the inflammatory responses. These drugs help reduce the swelling associated with the pain of headaches. During a migraine attack, emptying of the stomach is slowed, resulting in nausea and a delay in absorbing medication.

Ergotamines or ergot alkaloids (serotonin antagonists)

These are used to treat moderate migraine pain after analgesics and NSAIDs have proven to be ineffective. The absorption of ergotamines is increased by caffeine. They work effectively as competitive inhibitors by binding to a number of different neurotransmitter receptor systems, including 5-HT, dopamine and norepinephrine binding sites. They prevent serotonin from binding at these sites and themselves have no efficacy. Therefore the receptor is not activated and chemicals will cease to cause a migraine 4.

Dihydroergotamine (DHE) is an agonist of arterial serotonin receptors and blocks a-adrenergic receptors. DHE is hypothesised to exert an antimigraine effect by producing a powerful vasoconstriction of the external carotid artery and its branches, but also by a receptor-mediated neural pathway and a serotonergic mechanism [27] .

Triptans (serotonin agonists)

Sumatriptan - It can be taken via injection, pill or nasal spray. There have been two mechanism proposed for its method of action: vasoconstriction and trigeminal nerve inhibition. It is a potent vasoconstrictor of the intracranial arteries, a response to which can be produced even when a migraine attack is not taking place, showing that it has a direct vascular effect. It binds with high affinity to 5-HT1B and 5-HT1D receptors, activating and mediating vasoconstriction of the cranial vessels. On the other hand, sumatriptan can act directly within the cranial blood vessel on the trigeminal sensory nerve endings. [28] Another effect of sumatriptan is to reduce the plasma levels of calcitonin gene-related peptide (CGRP) which are raised during a migraine attack. This is a very useful attribute as some recent research demonstrated that CGRP may induce headache when infused to migraineurs [29] .

Future therapies

Although many of the medications I have discussed are effective in relieving migraine, they are far from the desired ideal anti-migraine medication. Regarding the acute treatment of attacks, the future for acquiring better efficacy and more specific actions seems promising. Several drugs and methods are currently under development. Many of them simply just current drugs that are being refined to cause less severe side effects or becoming more selective. Here are a few of the newly emerging methods being studied for treating migraine:

Nefazodone hydrochloride is a phenylpiperazine antidepressant with a distinct and unusual mechanism of action. It is a potent, selective 5-HT2 antagonist that moderately blocks serotonin and noradrenaline/norepinephrine reuptake, with a very low affinity for cholinergic, histaminic, or alpha-adrenergic receptors [30] .

Adenosine has an established antinociceptive effect in humans. Recent findings suggest that the analgesic effect of adenosine may be mediated by the adenosine A1 receptor.67 The relevance of these findings for human migraine is based on the recent observations that A1 receptor protein is localized in human trigeminal ganglia, and 2 selective A1 receptor agonists, GR79236 and GR190178, have been shown to inhibit the peripheral release of CGRP in the cranial circulation, as well as at the central trigeminal synapse, thereby preventing activation of central trigeminal neurons [31] .

Vanilloid receptors (VR1) - These are receptors that are activated by capsaicin, located on small- and medium-sized neurons that are either unmyelinated C-fibers or thinly myelinated A[DELTA]-fibers. They are found on neurons in the human trigeminal ganglia. Activation of the VR1 receptor could lead to CGRP-induced vasodilation at the trigeminovascular junction, thus making the VR1 receptor potentially a possible target for the development of antimigraine compounds [32] .

CGRP receptor antagonists - CGRP is one of many neuropeptides found inside cell bodies within the sensory terminals of the trigeminal nerve. Recent data suggest that CGRP receptor antagonists may provide acute relief of migraine headache [33] .

Glutamate receptor antagonists - The glutamate receptors may be metabotropic receptors (e.g. mGlu receptors groups I, II or III) or ionotropic (e.g. NMDA, AMPA and kainate (KA) types.) [34] LY293558 is an AMPA/KA receptor antagonist and has been tested for the treatment of migraine and pain. It had a 69% response rate on 44 of 45 of the volunteers it was tested on [35] .

In conclusion, a migraine is a disabling neurological disease, the cause of which is still not known. It is a very under-diagnosed disease mainly because it is difficult to record the full effects on patients as the migraine itself can last up to 72 hours, which is far longer then is spent being seen by a physician. The headache phase of migraine is thought to be associated with cerebral vasodilation and inflammation believed to be mediated by release of neuropeptides that include CGRP. A method of relieving these headaches is the injection of serotonin. Blood serotonin has been found to drop during migraine headaches. MAO inhibitors, which increase serotonin in the synapses, prevent migraine headaches, and medications that stimulate serotonin receptors relieve the acute pain. Migraine sufferers often report that the headaches stop after they have vomited, and it is this action that stimulates intestinal motility and raises blood serotonin. All of these facts suggest that low serotonin levels may influence migraine headaches. However a strong argument for the neuronal hyper-excitability, CSD and trigeminal theories all playing interlocking roles in the development on migraine is a very feasible one. Drugs acting on the early stages of migraine, as well as non-vasoactive therapies, are currently in the later stages of development, and we can hope to see some better results soon, but we are still some way off finding a full cure for migraine, as with many other major disabling diseases.

Fig 1 - Diagram showing the effect of the different neuropeptides in relation to migraine.

Hargreaves RJ, Shepheard SL. Pathophysiology of migraine - new insights. Can J Neurol Sci 1999;26(Suppl 3):S12-19