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Migraine and the pharmaceutical industry
Brain biochemistry and how migraine medicines work
Brain biochemistry and how migraine medicines work A number
of mechanisms have been proposed to account for how different
medicines help abort the onset or alleviate the symptoms of
migraine. This booklet will only consider the medicines which
act on the migraine headache itself, rather than other symptoms
such as sensitivity to light, sound or smell, nausea and other
types of pain.
The role of serotonin receptors: An enormous body
of data shows that several of the anti-migraine medicines,
including the triptans and ergotamine, act by stimulating
special binding sites on cell surfaces known as 5-HT1 receptors.
In a normal brain, these receptors function by binding a naturally-occurring
neurotransmitter called serotonin, which is another name for
5-HT: so in effect, the medicines mimic the action of serotonin.
Neurotransmitters are small chemicals which act as go-betweens
and pass electrical impulses from one nerve to the next or
from a nerve ending to another tissue such as a blood vessel
wall – rather like the baton passed by runners in a relay
race.
Other observations confirm that serotonin is involved in
migraine, notably:
- a sharp rise in the quantity of 5-HIAA, a breakdown
product of serotonin, observed in the urine during an
attack,
- a decline in blood serotonin levels during an attack,
- relief of migraines by the direct injection of serotonin,
- the artificial induction of a migraine following the
injection of a molecule such as reserpine that releases
serotonin from cells.
These observations began to be understood in the 1980s with
the discovery of several different kinds of serotonin receptor.
In particular, scientists found that migraine receptors differed
from those involved in other conditions. Further, it was found
that two sub-types of serotonin receptor were found to be
located in brain blood vessels and were responsible for their
constriction when stimulated. These are now known as 5-HT1B
and 5-HT1D.
5-HT1D receptors are concentrated at nerve endings in brain
blood vessels. The binding of serotonin to these receptors
after release from the nerves was found to block the release
of a peptide molecule called calcitonin gene-related peptide
(CGRP) that causes dilation of blood vessels, and also other
substances such as neurokinins. These trigger fluid leakage,
leading to the sterile inflammatory changes in the membrane
around the brain.
Confirmation of the role of these receptors in migraine came
when it was shown that ergotamine also stimulated them – thus
explaining its anti-migraine activity. Unfortunately, ergotamine
binds to several other receptor types which reduces its usefulness.
Clearly, the ideal molecule would be one that mimics serotonin
but does so without these unwanted actions.
These discoveries suggested that a medicine that mimicked
serotonin would be effective against the acute headache phase
of migraine, by reducing the dilation of blood vessels or
constricting those already dilated and inflamed. The search
for such a compound culminated with the discovery of sumatriptan
and has fuelled the research that has now led to the development
of several related compounds.
Other targets for anti-migraine medicines: This is
a complex and so far unresolved area of research, but much
evidence suggests that other receptors may be involved in
migraine and are potential sites for the design of new medicines.
For example, the existing triptans act on other serotonin
receptors and bind with varying strengths to 5-HT1B and 5-HT1D.
These differences may contribute to their varying effects.
Other evidence implicates receptors which bind a neurotransmitter
called gamma-amino butyric acid. GABA receptors are a site
of action for some of the anti-epilepsy medicines such as
valproate, which has some benefit in migraine prevention.
The glycine binding site of the NMDA receptor is yet another
possible target for developing preventive medicines and at
least one is in clinical trial.
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