Genetic and biochemical changes of the serotonergic system in migraine pathobiology

DOI: https://doi.org/10.1186/s10194- 016- 0711- 0

Abstract-Summary Attempts to study the biochemistry of migraine began as early as the 1960s and were primarily directed at serotonin metabolism after an increase of 5- hydroxyindoleacetic acid (5-HIAA), the main metabolite of serotonin was observed in urine of migraineurs.

Genetic and biochemical studies have primarily focused on the neurotransmitter serotonin, considering receptor binding, transport and synthesis of serotonin and

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have investigated serotonergic mediators including enzymes, receptors as well as intermediary metabolites.

These studies have been mainly assayed in blood, CSF and urine as the most

accessible fluids.

The general trend observed is that migraine patients have alterations of neu- rotransmitter metabolism detected in biological fluids with different biochemistry from controls, however the interpretation of the biological significance of these peripheral changes is unresolved.

We present the biology of the serotonergic system and metabolic routes for sero- tonin and discuss results of biochemical studies with regard to alterations in sero- tonin in brain, cerebrospinal fluid, saliva, platelets, plasma and urine of migraine patients.

Review We considered the biology of the serotonergic system and its metabolism and results of biochemical studies regarding the content of serotonin in the brain, cerebrospinal fluid (CSF), saliva, platelets, plasma and urine of migraine patients and we link the evidence together in a biochemical model that considers the application of metabo- lomics for guiding future research on the pathobiology of migraine.

The two most studied components of the serotonergic system that have come into the spotlight in determining susceptibility to migraine as well as multiple neuropsy- chiatric disorders are the serotonin transporter (SERT, also known as SLC6A4), which reuptakes serotonin from the synapse, and monoamine oxidase A (MAOA), an important enzyme that degrades serotonin and metabolizes triptans [43].

Park and others, in a pilot study of eight female migraine patients investigated the availability of SERT in the brain stem and concluded that migraineurs who experience more painful headaches have lower serotonin neurotransmission and additionally reported an age-related decline of SERT availability [44].

Conclusion The evidence so far points to migraine as a biochemically complex disorder involv- ing several neurotransmitter systems which converge in their synaptic pathways.

The general trend observed is that migraine patients have alterations of neu- rotransmitters in biological fluids with different biochemistry from controls, how- ever the interpretation of the biological significance of these peripheral changes is unresolved.

Novel approaches for investigating the serotonergic system using PET imaging technology integrated with a metabolomics and systems biology platform may help to better understand the biochemical milieu and metabolome of migraineurs and establish if the biochemical changes are linked to the clinical presentation of the disease process.

Given the therapeutic efficacy of triptans, investigating the functionality of the serotonergic system in the migraine brain remains on the agenda to illuminate dis- ease pathomechanisms and new lines of treatment to enable a superior understand- ing of the disease process that will further aid in the diagnosis, treatment and management of migraine and headache related disorders.

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Acknowledgement A machine generated summary based on the work of Gasparini, Claudia Francesca; Smith, Robert Anthony; Griffiths, Lyn Robyn. 2017  in The Journal of Headache and Pain.

New CACNA1A deletions are associated to migraine phenotypes