The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and γ-aminobutyric acid in fibromyalgia and healthy subjects: a multimodal neuroimaging study

• Published in: Pain (Amsterdam) Vol. 163; no. 2; pp. 274 - 286
• Main Authors: Fanton, Silvia, Sandström, Angelica, Tour, Jeanette, Kadetoff, Diana, Schalling, Martin, Jensen, Karin B., Sitnikov, Rouslan, Ellerbrock, Isabel, Kosek, Eva
• Format: Journal Article
• Language: English
• Published: United States Wolters Kluwer 01.02.2022
• Subjects: Brain; Endogenous pain modulation; Fibromyalgia; fMRI; GABA; gamma-Aminobutyric Acid - metabolism; Genetic polymorphism; Glutamate; Glutamic Acid - genetics; Glutamic Acid - metabolism; Healthy Volunteers; Humans; MRS; Neuroimaging; Pain - diagnostic imaging; Pain - genetics; Pain - metabolism; Positron-Emission Tomography - methods; rACC; Receptors, GABA - genetics; Receptors, GABA - metabolism; Research Paper; Thalamus; TSPO
• DOI: 10.1097/j.pain.0000000000002309
• ISSN: 0304-3959; 1872-6623

A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene ( rs6971 ) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). The influence of TSPO on endogenous pain modulation presented in the form of TSPO HABs, as opposed to MLABs, displaying less efficient descending pain inhibition and expectancy-induced reduction of pain. Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non–FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.