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Serotonin and its Role in Migraine Pathogenesis

Cassandra Farrar
Copyright 2012
Migraines are a debilitating neurovascular disorder that affects a
significant amount of people, with a higher occurrence rate seen in women than
in men. Migraines can vary in severity and symptoms, which can include:
persistent throbbing, nausea, vomiting, and light and sound sensitivity. Although
it is a common and chronic disorder, the true pathogenesis of migraines is
currently up for debate and has many plausible theories.
The earliest evidence of migraine dates back to Neolithic period circa
8500-7000 BC. People during this period commonly believed migraines were
caused by the supernatural and turned to trepanation for relief, and had circular
portions of their skulls removed so the spirits could escape. Early medical
documents reveal that in around 1200 BC, Egyptians relied on herbs and prayers
to alleviate pain caused by headaches. It wasnt until around 400 BC that
Hippocrates attributed migraines to actual medical reason; he believed
headaches were caused by vapors from the stomach rising to the head.i Since
then, much has been discovered about migraines but there are still areas of
uncertainty. One of the most important findings has been the identification and
discovery of the neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin.
Serotonin is one of the oldest neurotransmitters, in an evolutionary sense,
and is also one of the earliest to develop in the fetal brain. Serotonin is thought to

be involved with the etiology of many other disorders other than migraines, for
example depression, anxiety and schizophrenia. Serotonin is implicated in a
diverse range of behavioral and physiological functions such as sleep, appetite,
thermoregulation, mood, and notably pain perception. Serotonin is involved with
the bodys ability to induce pain by sensitizing pain receptors in the body.
Serotonin is also associated with the cranial vasoconstriction observed during
migraine attacks and also mediates many of the common migraine symptoms.ii
Serotonin also acts on a variety of membrane bound receptors, the majority of
which are G-protein-coupled receptors (GPCRs), and one that is a ligand-gated
ion channel.
Serotonin receptors are divided into seven classes based on their
structural and functional characteristics, denoted 5-HT1-5-HT7. Furthermore,
each class may consist of several subclasses denoted by an alphabetical letter.
Serotonin and its receptors can be found in the central and peripheral nervous
systems, as well as in several non-neuronal tissues found in the gastrointestinal
tract, cardiovascular system and in the blood.iii 5-HT1B/1D are both believed to be
involved in pain transmission during migraine and have received a lot attention in
pathophysiology and drug development of migraine, and will thus be the only
receptors that will be elaborated on in this paper.
In a study by J.D. Classey, T. Bartsch, and P.J. Goadsby, they wanted to
locate the exact distribution of 5-HT receptors in the peripheral nervous system in
rats. They made use of the peroxidase-avidin-biotin complex (ABC) for the
primary antibody, and a biotinylated secondary antibody. They found that 5-HT1B

and 5-HT1D were both present in trigeminal (5th cranial nerve) and dorsal root
ganglia (nodule containing neurons), and differences in cell staining indicated
different subtypes.iv The study also concluded that 5-HT1B/1D receptor antibodies
have specific targets and do not participate in any cross-reactivity with each
other. These results are particularly of importance for anti-migraine drug
treatment, which will be discussed later.
The serotonin pathway consists of several intermediates and enzymes.v
The amino acid tryptophan undergoes hydroxylation via tryptophan hyroxylase
(TH) to give rise to 5-hydroxytrptophan (5-HTP). This first step is the rate-limiting
step of serotonin synthesis.vi 5-HTP is decarboxylated into serotonin, 5-HT, via
aromatic L-Amino acid decarboxlyase (AADC). 5-HT is then catalyzed by
monoamine oxidase into 5-hydroxyindole acetaldehyde. And lastly, synthesis of
5-hydroxyindoleacetic acid (5-HIAA) is catalyzed by aldehyde dehydrogenase.vii
Studies have also shown that alterations in serotonin metabolism have been
associated with patients who suffer from migraines. Published in 1963, scientist
Federigo Sicuteri reported that high amounts of 5-HIAA were excreted in the
urine of patients on the day they had a migraine.viii Curran, Hinterberger and
Lance later confirmed these results in 1965ix, which reaffirms the biochemical
approach to migraine study. Circulating levels of 5-HIAA are also increased
during migraine.x
In a study published in 1968, M. Anthony reported that plasma levels of
serotonin during migraines had a sudden drop in 31 out of 33 patients studied.
This finding was also among the early implications of a possible relationship

between serotonin and migraines. These drops in 5-HT plasma levels occurred
at the onset of migraines and rose back to the normal level at the end of the
migraine attack. Secondly, low 5-HT plasma levels were unique to headaches
and did not occur during induced stressful events (that were not accompanied by
a headache).xi Anthonys study successfully suggested that serotonin plays a role
in the mechanism of migraine. These results also suggest that the metabolism of
serotonin is somehow altered.
Lastly, in a more recent study by E. Nagata et al., altered levels of
serotonin were studied in human lymphocytes. Lymphocytes were collected from
peripheral blood and were infected with Epstein-Barr viruses. These viruses
transformed the resting lymphocytes to infectiously proliferating cell lines, which
were then immortalized for studying purposes. They performed a Western Blot
analysis and treated the cells with antibodies to bind to 5-HT1B receptors, AADC,
TH, and serotonin transporters (SERT). These 5-HT related molecules and
enzymes are all apart of 5-HT metabolism. Horseradish peroxidase secondary
antibodies were also used. RNA was isolated and subjected to reverse
transcriptase polymerase chain reaction, RT-PCR, to determine which genes
were being expressed in the lymphoblasts. The measurements of 5-HT were
determined with a high performance liquid chromatography, HPLC, apparatus.
Their study showed that 5-HT1B, AADC, TH, and SERT were all found in
lymphocytes of migraine patients as well as the control. However, while most
data didnt produce significant differences between migraine and healthy
patients, 5-HT levels in migraine patients were significantly higher than the

control.xii These findings both confirm and indicate an alteration in 5-HT


metabolism in migraine patients.
Although scientists currently believe that serotonin plays a role in migraine
pathogenesis, the exact genesis of migraines is still not completely understood.
There are currently three theories for migraine pathogenesis: the vascular theory,
the neurological theory, and the neurovascular theory. The vascular theory
explains that migraines are due to vasodilatation, in which blood vessels are
dilated and blood pressure decreases during migraine. Secondly, the
neurological theory contributes migraines to neuronal events in different areas of
the brain. These events are believed to be mediated by an alteration in the
serotonin system. Lastly, the theory that migraines are due to a neurovascular
disorder suggest there is a neuronal dysfunction in which neuropeptides are
released from the trigeminal system causing dilation of meningeal vessels. Some
scientists believe migraines arise form brainstem and midbrain dysfunction due
to observed changes in electroencephalographies, or EEGsxiii . These theories
serve as a foundation in drug design and potential treatment.
Suggested treatment can either abolish the current headache, as in the
case of triptans, or aim to achieve prevention. Migraine drugs can either be nonspecific or specific. Non-specific drugs are meant to treat any accompanying
symptoms of the headache, whereas specific drugs produce selective
vasocontriction of extracranial blood vessels to alleviate the headache itself. In
the case of specific drugs, specific 5-HT receptors are of importance since the
drug should only selectively constrict cranial blood vessels in order to avoid

adverse effects. Therefore not surprisingly, all current and effective drugs are
selective vasoconstrictors.
The current major classes of antimigraine drugs are: antidepressants,
beta-adrenergic blockers (BABs), calcium channel blockers (CCBs) and
antiepileptic drugs (AEDs).xiv Since serotonin has been shown to be involved with
migraine attacks, a lot of attention has be given to both serotonin antagonists and
agonists. Antagonists are substances that interfere or inhibit the action of another
substance. While agonists do the opposite and they initiate a physiological
response when combined with its receptor. Important known antagonists are:
ergotamine, methysergide, pizotigen, cyproheptadine, lisuride, mianserin, and
ketanserin. All of these are competitive inhibitors of serotonin and are used in
migraine prevention.xv
One class of drugs involved in abolishing headaches and have proved to
be of great importance in migraine study are the triptans. Triptans have high
binding affinities for 5-HT1 receptors, mainly 5-HT1B/1D. 5-HT1B is a composite of
two types encoded by two distinct genes. The human 5-HT1B receptor is
homolgous to the rodent 5-HT1B receptor but they differ by a single amino acid in
the transmembrane region: an Asp instead of an Arg. 5-HT1B is expressed in the
CNS and is concentrated in the basal ganglia, striatum and frontal cortex. 5-HT1B
is a heteroreceptor, meaning it controls the release of other neurotransmitters
such as acetylcholine, glutamate, dopamine, noradrenaline and -aminobutric
acid. Lastly, 5-HT1D is present in the dorsal raph nuclei and in the human heart,
where it modulates 5-HT release.xvi

In addition to having high binding affinities for serotonin receptors, triptans


also have other antimigraine characteristics that contribute to their overall
effectiveness. These characteristics include: vasoconstriction of the dilated
extracerebral vessels by a direct effect on vascular smooth muscle (via 5-HT1B
agonist), inhibition of neuropeptide release, and inhibition of neurological pain
within the brainstem and upper spinal cord (via 5-HT1D agonist).xvii Some
examples of triptans include: sumatriptan, zolmitriptan, naratriptan, rizatriptan
almotriptan, frovatriptan, and eletriptan. Triptans have high clinical value and
efficacy not only because of their agonist effects, but also because of their high
oral bioavailability, quick onset of action, and minimal adverse effects.
Triptans are the most specific pharmacological treatment for
neurovascular headaches, i.e. migraines and cluster headaches.xviii That is, they
dont act on any other types of pain, or even other specific types of headaches
such a tension headaches. To test for this, A. Ottani et al. provoked different
models of pain in rats and treated them with sumatriptan. Sumatriptan is a very
popular 5-HT1B/1D agonist that acts both at peripheral and central sites.xix A.
Ottani et al. conducted a hot-plate test, an abdominal constriction test, and lastly
they induced migraines in each of the rats. Sumatriptan, as well morphine and
indomethacin, were subcutaneously administered in varying dosages.
Sumatriptan had no effect at any dose in the rats that had induced pain from the
hot plate and abdominal constriction test, whereas morphine and indomethacin
did. On the contrary, sumatriptan alleviated migraine pains, whereas morphine
and indomethacin had no to little effect on the rats. These results conclude that

sumatriptan alleviates pain specifically via 5-HT receptors thus implying that
serotonin is involved in the migraine pathophysiology. This study also suggests
that sumatriptan produces dose-dependent analgesic effects.xx
While scientists are still looking for a solid explanation for migraines, much
has been achieved both in theory and treatment. However, one of the biggest
uncertainties that revolves around the pathogenesis of migraines is the wide
range of triggers patients seem to have. These triggers imply a highly sensitive
mechanism or varying mechanisms that can all lead a migraine attack. As
studies lead to more findings about serotonin, and possibly other critical agents
involved, drug treatments can become even more effective and patients can
minimize their pain and hopefully minimize the occurrences of migraines as well.


i
Villaln CM et al., Migraine: Pathophysiology, Pharmacology, Treatment, Future
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ii

Sicuteri F, Hypothesis: Migraine, A Central Biochemical Dysnociception.


Headache, (1976) 16: 145-159.

iii

Hoyer D, JP Hannon and GR Martin. Molecular, Pharmacological, and


Functional Diversity of 5-HT Receptors. Pharmacology Biochemistry and
Behavior, (2002) 71: 4, 533-554.

iv

Classey, JD, T Bartsch, and PJ Goadsby. Distribution of 5-HT1B, 5-HT1D and


5-HT1F receptor expression in rat trigeminal and dorsal root ganglia neurons:
Relevance to the selective anti-migraine effect of triptans. Brain Research,
(2010) 1361: 76-85.

Anthony M. Serotonin Antagonists. Australian and New Zealand Journal of


Medicine, (1984) 14: 6, 888-895.


vi
E Nagata et al. Altered levels of serotonin in lymphoblasts derived form
migraine patients. Neuroscience Research, (2007) 57: 179-183.
vii

Anthony M, Serotonin Antagonists. Australian and New Zeland Journal of


Medicine, (1984) 14: 6, 888-895.
viii

Sicuteri F, Mast Cells and their Active Substances. Headache (1963) 3, 86-92.

ix

Anthony M, H Hinterberger, and JW Lance. Studies or Serotonin Metabolism in


Migraine. Proceedings of the Australian Association of Neurologists, (1968) 5:
1, 109-112.

Tepper SJ, AM Rapoport, and FD Sheftell. Mechanisms of Action of the 5HT1B/1D Receptor Agonists. Archives of Neurology, (2002) 59: 7, 10841088.

xi

Anthony M, Plasma Serotonin Levels in Migraines. Advances in Pharmacology,


(1968) 6, 203.

xii

E Nagata et al. Altered levels of serotonin in lymphoblasts derived form


migraine patients. Neuroscience Research, (2007) 57: 179-183.

xiii

Sand T et al. Brainstem auditory-evoked potential habituation and intensitydependence related to serotonin metabolism in migraine: A longitudinal study.
Clinical Neurophysiology, (2008) 119: 1190-1200.

xiv

Galleti F et al., Pathophysiological Basis of Migraine Prophylaxis. Progress in


Neurobiology, (2009), 89: 2, 176-192.

xv

Anthony M, Serotonin Antagonists. Australian and New Zeland Journal of


Medicine, (1984) 14: 6, 888-895.

xvi

Hayer D, JP Hannon and GR Martin. Molecular, Pharmacological, and


Functional Diversity of 5-HT Receptors. Pharmacology Biochemistry and
Behavior, (2002) 71: 4, 533-554.

xvii

Tepper SJ, AM Rapoport, and FD Sheftell. Mechanisms of Action of the 5HT1B/1D Receptor Agonists. Archives of Neurology, (2002) 59: 7, 10841088.

xviii

Ottani A et al. Effects of sumatriptan in different models of pain in rats.


European Journal of Pharmacology, (2004) 497: 181-186.

xix

Jennings EA, RM Ryan, and MJ Christie. Effects of sumatriptan on rat


medullary dorsal horn neurons. Pain, (2004) 111: 30-37.


xx

Ottani A et al. Effects of sumatriptan in different models of pain in rats.


European Journal of Pharmacology, (2004) 497: 181-186.