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Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity

Zunhammer, Matthias; Schweizer, Lauren M.; Witte, Vanessa; Harris, Richard E.; Bingel, Ulrike; Schmidt-Wilcke, Tobias

doi: 10.1097/j.pain.0000000000000634
Research Paper

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher–Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Supplemental Digital Content is Available in the Text.Levels of combined glutamate and glutamine, but not γ-aminobutyric acid within pain-related brain regions of healthy subjects are positively correlated with experimental pain sensitivity.

aKlinik für Neurologie, Universitätsklinikum Essen, Essen, Germany

bAbteilung für Neurologie, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Bochum, Germany

cDepartment of Anesthesiology, University of Michigan, Ann Arbor, MI, USA

Corresponding author. Address: Klinik für Neurologie, Universitätsklinikum Essen, Hufelandstraβe 55, 45147, Essen, Germany. Tel.: +49 176 60016738; fax: +49 201 723 6882. E-mail address: (M. Zunhammer).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

Received March 21, 2016

Received in revised form May 13, 2016

Accepted May 26, 2016

© 2016 International Association for the Study of Pain
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