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

Review Article

Austin J Clin Neurol 2015; 2(9): 1079.

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

Gasparini CF¹, Smith RA² and Griffiths LR*

¹Menzies Health Institute Queensland, Griffith University Gold Coast, Australia

²Genomics Research Centre, Queensland University of Technology, Australia

*Corresponding author: Griffiths LR, Genomics Research Centre, Institute of Health and Biomedical Innovation, Queensland University of Technology, Musk Ave, Kelvin Grove, QLD, 4059, Australia

Received: August 10, 2015; Accepted: October 30, 2015; Published: November 20, 2015


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.

Keywords: Migraine; Migraine with aura; Migraine without aura; Glutamate; Neurotransmitters; Platelets


CSD: Cortical Spreading Depression; MSG: Monosodium Glutamate; TCA: Tricarboxylic Acid; GS: Glutamine Synthetase; CRS: Chinese Restaurant Syndrome; NMDA: N-Methyl-D-aspartate; CSF: Cerebrospinal Fluid; MA: Migraine with Aura; MO: Migraine without Aura; TH: Tension Headache Patients; PRP: Platelet-rich Plasma; HVA: Homovanillic Acid; 5-HIAA: 5-Hydroxyindoleacetic Acid; FM: Fibromyalgia; CDH: Chronic Daily Headache; CM: Chronic Migraine; CH: Cluster Headache; CMF: Chronic Migraine with Fibromyalgia; PLTS: Platelets; RBC: Red Blood Cells


Glutamate, like serotonin and dopamine is a prominent neurotransmitter in the CNS that mediates fast excitatory synaptic neurotransmission via ionotropic and metabotropic receptors [1]. Glutamatergic receptors are the molecular mediators through which glutamate acts and are found in the trigeminovascular system and its structures [2,3]. Glutamate is stored intracellularly inside synaptic vesicles where the concentration may be as high as 100 millimolars and is inactive until released into the synapse [4]. Glutamate is believed to be required for cortical spreading depression and to activate the trigeminovascular system and central sensitization [5-7] is a substrate for various enzymes at glutamatergic synapses and is at a crossroads of metabolic pathways acting as a precursor of the inhibitory neurotransmitter GABA and being involved in brain energy metabolism and nitrogen homeostasis [8]. There are two pathways through which glutamate can be synthesized: the majority is synthesised from glutamine deamidation via the enzyme glutaminase and to a lesser extent approximately one-third is derived from glucose via tricarboxylic acid (TCA) cycle intermediates (α- ketoglutarate) and transamination with GABA [9]. In addition to glutamate receptors and transporters, there are enzymes, such as glutamine synthetase (GS) that control the levels of intracellular glutamate, for example through the conversion of glutamate to glutamine [10].

Accumulating data from genetic studies demonstrate that migraineurs have a perturbed glutamatergic system, which may be reflected in the brain as neuronal hyperexcitability [11]. There is also accumulating evidence that glutamate receptors exhibit a modulatory effect in migraine mechanisms and glutamate modulating therapies have shown promise on migraine symptoms [12]. The glutamatergic system in migraine patients may be compromised and this may occur as a consequence of polymorphisms in genes that regulate glutamatergic signalling. Currently there is only evidence to implicate the GRIA3 gene of the AMPA receptor, but time will tell if there are more polymorphisms in these or other genes to be identified [13,14]. The peripheral metabolism of glutamate which includes the production, storage, expression, trafficking and function of ionotropic glutamate receptors and glutamate is just as important as is the neuronal component of glutamate in the brain and may also have a bearing on migraine. The hypothesis is that migraineurs have a propensity for genetically disordered glutamatergic neurotransmission.

Migraine is a multi-system disorder with vascular, inflammatory, neurological and biochemical components that culminate in central neuronal hyperexcitability, which is the underlining mechanism most often targeted in pharmacological intervention [15]. The ideal situation for diagnosis and treatment of migraine would be to have biomarkers which can reliably distinguish those with disease from healthy individuals [16]. The genetic evidence for glutamate’s involvement in migraine and our knowledge of its biochemical role gives it potential to be such a biomarker for migraine. At present, however, the development and adoption of glutamate or glutamaterelated biomarkers is slow and currently there are no validated biomarkers for measuring glutamate pathology in CNS injuries or disorders, including migraine [16-18]. More precise characterization of the glutamate molecular-signaling pathways in glutamatergic cells is warranted as a prerequisite for understanding the potential involvement of the glutamatergic system in the aetiology of migraine. The goal of this short review is to summarize the biochemical findings of the neurotransmitter glutamate in migraine to help facilitate further research which may enable its use as a migraine biomarker.

Glutamate Biochemical Studies

Monosodium glutamate

Glutamate produced outside of the human body is best known as “monosodium glutamate” (MSG) which is sodium salt of glutamic acid [19]. MSG is a well-known food additive and flavor enhancer that has been used for more than 100 years in Asian cuisine due to the umami (savory) taste it gives to food [20]. Binding of MSG to a specific metabotropic glutamate receptor, different from the receptors for sweet, salty, sour, and bitter, is thought to be responsible for this fifth gustatory sensation [21]. Aside from being synthesized as a food additive, MSG is also naturally occurring at high levels in some foods such as tomato and cheese. The human body prefers to use L-glutamic acid which is the naturally-occurring predominant form of glutamate. The second form of glutamic acid, the D-enantiomeric form D-glutamic acid, is found naturally only in the cell walls of certain bacteria [22]. Manufactured/processed MSG typically contains L-glutamic acid in addition to the D-enantiomer D-glutamic acid and a mixture of impurities of pyroglutamic acid, mono and dichloro propanols and heterocyclic amines [23,24]. Further research regarding the impact of D-amino acid metabolism with the normal metabolism of L-amino acids is necessary in view of the fact that some studies have shown that when D-glutamate is given to mice in large doses it can suppress immunological activity [25].

Early reports claimed that MSG may be the cause of headache and Alfred Scopp in 1991 published a study “MSG and hydrolyzed vegetable protein induced headache: review and case studies” questioning the connection between MSG and headache [26]. According to this study, MSG, tyramine and aspartame were found to be migraine triggers in susceptible individuals [26]. This observation is supported by discussion in the published literature of the Chinese Restaurant Syndrome (CRS) now better known as the MSG symptom complex [27]. MSG symptom complex refers to a triad of symptoms first reported in 1968 after ingestion of a Chinese meal [28]. The symptoms experienced were described as “numbness at the back of the neck and arms gradually radiating to the arms and the back, general weakness, and palpitations” and were thought to be brought on by ingestion of food rich in MSG in particular Chinese cuisine [29]. Based on these observations researchers have investigated the potential relationship between MSG and headache and the MSG symptom complex in various studies in animals and humans.

MSG injected intravenously into rats has been shown to raise intramuscular tissue concentrations of glutamate through activation of N-methyl-D-aspartate (NMDA) receptors [6,30]. Elevated tissue concentrations of glutamate have been shown to contribute to pain and sensitivity in certain musculoskeletal pain conditions [31]. Baad- Hansen et al., 2009 investigated the influence of an oral dose of MSG based on each individual subject’s body weight, administered to 14 young healthy male volunteers and the occurrence of headache, sideeffects, sensitivity to pressure pain in masseter and temporalis muscles, blood pressure and heart rate were assessed [32]. This study reported a significant increase in subjects’ self-reported symptoms of headache and pericranial muscle tenderness after ingestion of MSG, as well as increased systolic blood pressure. Similarly and more recently Shimada et al., 2013 [33] conducted a double-blind, placebocontrolled, crossover study to look at the effect of MSG intake on spontaneous headache. The conclusion reached was that subjects consuming MSG had higher systemic levels of glutamate and that this is the reason participants were more likely to suffer from headache and have accompanying masseter muscle sensitivity. Overall, neurotoxicity by MSG has been demonstrated in animals and various studies in humans have investigated reports of adverse reactions to MSG with high doses however, the symptoms reported in these studies are neither persistent nor serious. Consequently, the data on the relationship between MSG and migraine headache is still inconclusive and a causal relationship has not explicitly been identified and further investigation is warranted [27,34-36]. Although a subset of the population react adversely to MSG and are termed “MSG sensitive individuals” who have experienced adverse reactions which include skin rash, tachycardia, migraine headache, depression, and seizures, altogether the literature agrees there is inadequate evidence to establish MSG as a causative factor of migraine headache [23].


In the last 30 years, biochemical studies investigating glutamate levels in plasma, platelets, CSF and urine of migraine patients have reported significantly higher glutamate concentrations particularly in patients with migraine with aura. The main source of glutamate is from neurons however, in the periphery, plasma glutamate mostly derives from freely circulating platelets which accumulate glutamate [37]. Blood plasma is the pale yellow liquid portion of blood in which blood cells are suspended and nutrients are dissolved, contributing 55% of the body’s total blood volume [38].

Thus far, five studies out of seven have reported higher plasmatic levels of glutamate in migraine patients between and during attacks with the study by Alam et al., 1998 [39] having the largest sample size consisting of 80 migraine with aura (MA), 9 migraine without aura (MO) and 14 Tension Headache (TH) patients (Table 1). The largest sample size was 103 and the smallest 24, the average sample size in the seven studies using plasma as sample was 48, showing a range of studies with various capabilities to detect alterations in glutamate metabolism. Moreover, plasma glutamate is likely to be linked to the platelet glutamate storage function, and individual differences in this mechanism may add additional variation to observed glutamate levels [40,41]. Factors which can further confound the accurate reporting of plasma glutamate levels include differences in experimental procedures, such as different concentrations of inducers, centrifugation time and pharmaceutical substances produced by different manufacturers, different timing of blood sampling (time of day, menstrual cycle, time passed since the last attack, fasting/non-fasting), blood-drawing and samplehandling protocols (venipuncture-induced platelet activation, body position, blood sample device: open system/vacutainer, operators’ experience, time of stasis), patient drug history and diet [42,43].

Citation: Gasparini CF, Smith RA and Griffiths LR. Biochemical Studies of the Neurotransmitter Glutamate: A Key Player in Migraine. Austin J Clin Neurol 2015; 2(9): 1079. ISSN : 2381-9154