title: Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes.
abstract: Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.
authors.affiliation: Department of Clinical Neuroscience, Osher Center, Karolinska Institutet, Stockholm, Sweden.|Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Tour
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden.|Department of Rehabilitation Medicine, Danderyd Hospital, Stockholm, Sweden.
authors.forename: Monika
authors.initials: M
authors.lastname: Löfgren
authors.affiliation: Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Mannerkorpi
authors.affiliation: Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Gerdle
authors.affiliation: Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.|Centre for Person Centered Care (GPCC), University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anette
authors.initials: A
authors.lastname: Larsson
authors.affiliation: Department of Health and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annie
authors.initials: A
authors.lastname: Palstam
authors.affiliation: Department of Clinical Sciences, Karolinska Institutet, Stockholm, Sweden.|Pain and Rehabilitation Centre, and Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Indre
authors.initials: I
authors.lastname: Bileviciute-Ljungar
authors.affiliation: Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Bjersing
authors.affiliation: Department of Clinical Neuroscience, Osher Center, Karolinska Institutet, Stockholm, Sweden.|Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Ingvar
authors.initials: I
authors.lastname: Martin
authors.affiliation: Department of Dental Medicine, Karolinska Institutet, Scandinavian Center for Orofacial Neurosciences (SCON), Huddinge, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Ernberg
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.affiliation: Department of Clinical Neuroscience, Osher Center, Karolinska Institutet, Stockholm, Sweden.|Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.|Stockholm Spine Center, Lowenstromska Hospital, Upplands Vasby, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Kosek
mesh_terms: D000328:Adult; D000483:Alleles; D004843:Epistasis, Genetic; D005081:Exercise Therapy; D005260:Female; D005356:Fibromyalgia / Q000235:genetics* / Q000628:therapy; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010146:Pain / Q000235:genetics*; D059408:Pain Management; D010147:Pain Measurement; D017288:Pain Threshold / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D011312:Pressure; D011401:Promoter Regions, Genetic; D044282:Receptor, Serotonin, 5-HT1A / Q000235:genetics*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C485764:OPRM1 protein, human; D017450:Receptors, Opioid, mu; D050486:Serotonin Plasma Membrane Transport Proteins; D044282:Receptor, Serotonin, 5-HT1A