Cerebrospinal Fluid Glutamate Levels in Chronic Migraine

Hospital Israelita Albert Einstein, Instituto de Ensino e Pesquisa, São Paulo, Brazil.
Cephalalgia (Impact Factor: 4.89). 10/2004; 24(9):735-9. DOI: 10.1111/j.1468-2982.2004.00750.x
Source: PubMed


Both preclinical and clinical data link glutamate to the migraine pathophisiology. Altered plasma, platelets and cerebrospinal (CSF) glutamate levels have been reported in migraine patients. Chronic migraine is comorbid with several conditions. It has been recently shown chronic migraine comorbidity with fibromyalgia. The objective of this study was to study cerebrospinal fluid glutamate levels in chronic migraine patients with and without fibromyalgia. We studied 20 chronic migraine patients, with and without fibromyalgia, compared to age-sex matched controls. CSF glutamate levels were measured by HPLC. CSF glutamate demonstrated significantly higher levels in patients with fibromyalgia compared to those without fibromyalgia. Patients overall had higher CSF glutamate levels than controls. Mean pain score correlated with glutamate levels in chronic migraine patients. Tender points, the hallmark of fibromyalgia, can be considered as pressure allodynia, and is probably mediated by central sensitization, with increase in CSF glutamate levels. We postulate chronic migraine patients with fibromyalgia, in addition to have more disabling headaches, suffer from a more severe central sensitization process. This subtype of patients may respond to medications modulating glutamate receptors. Headache intensity correlate with glutamate levels in chronic migraine patients.

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    • "Ramadan found that glutamate facilitates cortical spreading depression (CSD), central sensitization, which are the central mechanisms for triggering migraine [37]. Peres et al. have shown that plasma glutamate levels are positively correlated with headache intensity in chronic migraine patients [38, 39]. Accordingly, our study further demonstrates that the elevation of glutamate in the plasma is a crucial contributory factor in acute migraine attack. "
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    ABSTRACT: Background. The objective of this study was to identify potential biomarkers of electroacupuncture (EA) on relieving acute migraine through metabolomic study. Methods. EA treatments were performed on both acupoints and nonacupoints on the nitroglycerin (NTG)-induced migraine rat model. NMR experiments and multivariate analysis were used for metabolomic analysis. Results. The number of head-scratching, the main ethology index of migraine rat model, was significantly increased (P < 0.01) after NTG injection. The plasma metabolic profile of model group was distinct from that of the control group. Glutamate was significantly increased (P < 0.01), whereas lipids were significantly decreased (P < 0.01) in model rats. After EA at acupoints, the metabolic profile of model rats was normalized, with decreased glutamate (P < 0.05) and increased lipids (P < 0.01). In contrast, EA at nonacupoints did not restore the metabolic profile, but with six metabolites significantly different from acupoints group. Interestingly, the number of head-scratching and glutamate level were significantly decreased (P < 0.05) after receiving EA at both acupoints and nonacupoints. Conclusions. EA at acupoints may relieve acute migraine by restoring the plasma metabolic profile and plasma glutamate, while EA at nonacupoints may modestly relieve acute migraine by decreasing plasma glutamate.
    Evidence-based Complementary and Alternative Medicine 01/2014; 2014:659268. DOI:10.1155/2014/659268 · 1.88 Impact Factor
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    • "These results are consistent with those of previous in vitro and in vivo studies showing that chronic pain elevates glutamate release in the mPFC [14] [72] [73]. Similarly, an increased glutamate level in the cerebrospinal fluid has been found in patients with persistent pain [36] [53]. Pathological pain-induced central sensitization involves enhanced presynaptic glutamate release and requires increased postsynaptic receptor-mediated responses [61] [72]. "
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    ABSTRACT: Although nerve injury-induced long-term postsynaptic changes have been investigated, less is known regarding the molecular mechanisms within presynaptic axonal terminals. We investigated the molecular changes in presynaptic nerve terminals underlying chronic pain-induced plastic changes in the medial prefrontal cortex (mPFC). After neuropathic pain was induced by a spared nerve injury (SNI) in rats, we assessed the release of excitatory neurotransmitter glutamate by using in vitro synaptosomal preparation from the mPFC. We also measured the levels of synaptic proteins and protein kinases in synaptosomes by using Western blot. The results showed that unilateral long-term SNI augmented depolarization-evoked glutamate release from synaptosomes of the bilateral mPFC. This result was confirmed by a rapid destaining rate of FM1-43 dye in SNI-operated rats. Unilateral long-term nerve injury also significantly increased synaptic proteins (including synaptophysin, synaptotagmin, synaptobrevin, syntaxin, and SNAP-25) in synaptosomal fractions from the bilateral mPFC, and ultrastructure images demonstrated increased synaptic vesicular profiles in synaptosomes from SNI animals. Chronic pain upregulated the phosphorylation of endogenous protein kinases, including extracellular signal-regulated kinases 1 and 2 (ERK1/2) and Ca(2+)/calmodulin-dependent kinase II (CaMKII), and synapsin I, the primary presynaptic target of ERK1/2 and CaMKII. Both presynaptic proteins and protein kinases were upregulated after SNI in a time-dependent manner. These results indicate that the long-term neuropathic pain-induced enhancement of glutamate release in the mPFC is linked to increased synaptic vesicle proteins and the activation of the ERK1/2- and CaMKII-synapsin signaling cascade in presynaptic axonal terminals.
    Pain 11/2013; 155(2). DOI:10.1016/j.pain.2013.10.026 · 5.21 Impact Factor
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    • "CSF concentrations of substance P and glutamate have been repeatedly found to be increased in fibromyalgia patients [32] [33] [34]. With respect to glutamate, proton magnetic resonance spectroscopy studies could show that this neurotransmitter is elevated in pain processing regions such as the insula, amygdala, and cingulate cortex [35] [36] [37] [38] [39]. Supporting the hypothesis that a hyperactive glutamate system contributes to increased pain sensitivity, and maybe other symptoms of fibromyalgia, elevated glutamate levels in the insular cortex have been observed to be correlated with low pressure pain thresholds [39] as well as with high scores on the fibromyalgia impact questionnaire (FIQ, [40]) [37]. "
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    ABSTRACT: Fibromyalgia is considered a stress-related disorder, and hypo- as well as hyperactive stress systems (sympathetic nervous system and hypothalamic-pituitary-adrenal axis) have been found. Some observations raise doubts on the view that alterations in these stress systems are solely responsible for fibromyalgia symptoms. Cumulative evidence points at dysfunctional transmitter systems that may underlie the major symptoms of the condition. In addition, all transmitter systems found to be altered in fibromyalgia influence the body's stress systems. Since both transmitter and stress systems change during chronic stress, it is conceivable that both systems change in parallel, interact, and contribute to the phenotype of fibromyalgia. As we outline in this paper, subgroups of patients might exhibit varying degrees and types of transmitter dysfunction, explaining differences in symptomatoloy and contributing to the heterogeneity of fibromyalgia. The finding that not all fibromyalgia patients respond to the same medications, targeting dysfunctional transmitter systems, further supports this hypothesis.
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