title: The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia.
abstract: The translocator protein (TSPO) is upregulated during glia activation in chronic pain patients. TSPO constitutes the rate-limiting step in neurosteroid synthesis, thus modulating synaptic transmission. Related serotonergic mechanisms influence if pro- or anti-nociceptive neurosteroids are produced. This study investigated the effects of a functional genetic polymorphism regulating the binding affinity to the TSPO, thus affecting symptom severity and cerebral pain processing in fibromyalgia patients. Gene-to-gene interactions with a functional polymorphism of the serotonin transporter gene were assessed. Fibromyalgia patients (n=126) were genotyped regarding the polymorphisms of the TSPO (rs6971) and the serotonin transporter (5-HTTLPR/rs25531). Functional magnetic resonance imaging (n=24) was used to study brain activation during individually calibrated pressure pain. Compared to mixed/low TSPO affinity binders, the high TSPO affinity binders rated more severe pain (p=0.016) and fibromyalgia symptoms (p=0.02). A significant interaction was found between the TSPO and the serotonin transporter polymorphisms regarding pain severity (p<0.0001). Functional connectivity analyses revealed that the TSPO high affinity binding group had more pronounced pain-evoked functional connectivity in the right frontoparietal network, between the dorsolateral prefrontal area and the parietal cortex. In conclusion, fibromyalgia patients with the TSPO high affinity binding genotype reported a higher pain intensity and more severe fibromyalgia symptoms compared to mixed/low affinity binders, and this was modulated by interaction with the serotonin transporter gene. To our knowledge this is the first evidence of functional genetic polymorphisms affecting pain severity in FM and our findings are in line with proposed glia-related mechanisms. Furthermore, the functional magnetic resonance findings indicated an effect of translocator protein on the affective-motivational components of pain perception.
authors.affiliation: Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden; Stockholm Spine Center, Löwenströmska Hospital, 198 84 Upplands Väsby, Sweden. Electronic address: Eva.Kosek@ki.se.
authors.forename: Eva
authors.initials: E
authors.lastname: Kosek
authors.affiliation: Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden. Electronic address: Sofia.Martinsen@ki.se.
authors.forename: Sofia
authors.initials: S
authors.lastname: Martinsen
authors.affiliation: Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden. Electronic address: Bjorn.Gerdle@liu.se.
authors.forename: Björn
authors.initials: B
authors.lastname: Gerdle
authors.affiliation: Department of Health and Rehabilitation/Physiotherapy, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden; University of Gothenburg Centre for Person-centred Care (GPCC), Sahlgrenska Academy, Gothenburg, Sweden. Electronic address: Kaisa.Mannerkorpi@neuro.gu.se.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Mannerkorpi
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet and Department of Rehabilitation Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden. Electronic address: Monika.Lofgren@ki.se.
authors.forename: Monika
authors.initials: M
authors.lastname: Löfgren
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet and Department of Rehabilitation Medicine, Danderyd Hospital, SE-182 88 Stockholm, Sweden. Electronic address: indre@ljungar.se.
authors.forename: Indre
authors.initials: I
authors.lastname: Bileviciute-Ljungar
authors.affiliation: Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden. Electronic address: Peter.Fransson@ki.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Fransson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: Martin.Schalling@ki.se.
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden. Electronic address: Martin.Ingvar@ki.se.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, and Scandinavian Center for Orofacial Neurosciences (SCON), SE-141 04 Huddinge, Sweden. Electronic address: Malin.Ernberg@ki.se.
authors.forename: Malin
authors.initials: M
authors.lastname: Ernberg
authors.affiliation: Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden. Electronic address: Karin.Jensen@ki.se.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Jensen
mesh_terms: D000328:Adult; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D005260:Female; D005356:Fibromyalgia / Q000235:genetics* / Q000503:physiopathology*; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000503:physiopathology; D010146:Pain / Q000235:genetics*; D010147:Pain Measurement; D058748:Pain Perception / Q000502:physiology*; D011110:Polymorphism, Genetic; D018079:Receptors, GABA / Q000235:genetics* / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D018079:Receptors, GABA; D050486:Serotonin Plasma Membrane Transport Proteins; C499229:TSPO protein, human
keywords: 5-HTTLPR; Fibromyalgia; Functional magnetic resonance imaging; Gene-to-gene interactions; Genetic polymorfisms; SCL6A4; Serotonin; Serotonin transporter; Translocator protein; rs6971