Biochemical Studies of the Neurotransmitter Glutamate: A Key Player in Migraine

Susceptibility to migraine is influenced by a multitude of factors including gene-environment and gene-gene interactions. The emerging picture of migraine pathogenesis is that it is a complex polygenic and heterogeneous disorder at both the population and molecular levels. Causes of migraine are not very clearly understood and therefore research into the aetiology of migraine takes several different approaches including genetic, pharmacological and biochemical to integrate disease based information on multiple levels. Neurotransmitters have been implicated in migraine pathogenesis, in particular the excitatory transmitter glutamate with supporting evidence from GWAS and genotyping case-control studies. The brain contains large amounts of glutamate, a plentiful excitatory amino acid neurotransmitter necessary to the integrity of synaptic plasticity and memory in CNS functioning, which is highly toxic to neurons if present for prolonged periods. Glutamate has been implicated in cortical spreading depression (CSD) in animal models and the ingestion of glutamate in the form of monosodium glutamate in predisposed individuals can elicit sensitivity and migraine-like headache (the MSG Symptom Complex). Comparisons between migraine patients and normal controls on biochemical measures in a range of biological fluids have shown significant differences between these groups particularly in migraineurs with aura. Despite the observation of notable biochemical alterations, specific diagnostic markers are lacking. In this review we discuss biochemical findings in plasma, platelets, saliva, cerebrospinal fluid, and urine that support the conception that a component of glutamate receptor disruption may contribute to migraine susceptibility.