The importance of genetic polymorphisms in the pathophysiology of fibromyalgia

Fibromyalgia (FM) is a complex and chronic nociplastic pain disease characterized by long- term widespread pain. Mechanisms involved are both central and peripheral including dysfunctional central pain modulation, and recently studies of autoimmune mechanisms has provided novel insights. The aim of this thesis was to explore the genetic underpinnings of FM, focusing on polymorphisms in pain-related genes and their influence on pain intensity and pain modulation. The studies within this thesis investigate the influence of and interactions between opioid, serotonergic, monoamine and neuroimmune mechanisms to understand their potential roles in the pathophysiology of FM.

Study I examined polymorphisms in the OPRM1 gene, which encodes the u-opioid receptor (MOR), and serotonergic genes coding for the serotonin transporter (5-HTT) and serotonin receptor 1a (5-HT1a) in relation to pain modulation assessed by exercise-induced hypoalgesia (EIH), using isometric exercise as the conditioning stimulus. The results demonstrated that individuals with the OPRM1 G-genotype, particularly in combination with low-expressing 5-HTT or the 5-HT1a G-genotype, exhibited better functioning EIH regardless of whether the individual was an FM patient or a healthy control (HC). This suggests that the genetic interaction between opioid and serotonergic mechanisms is associated with the modulation of pain, independent of baseline pain status.

Study II investigated the same genetic polymorphisms as study I, but the measure of pain modulation was conditioned pain modulation (CPM) with ischemic pain as the conditioning stimulus and pressure pain as the test stimulus. The main finding was that individuals with the OPRM1 G-genotype had a significantly reduced ability to activate CPM. This finding suggests that individuals with the G-genotype may have a reduced ability to engage descending pain inhibitory pathways, which is a key feature in the pathology of FM. In agreement with study I, there was an interaction between the OPRM1 polymorphism and the 5-HT1a polymorphism. Also, this effect was observed consistently across both FM patients and HC, with no significant differences between the groups. These findings highlight the importance of the interaction between opioid and serotonergic mechanisms in regulating pain modulation, regardless of the presence of FM.

Study III explored cerebral pain processing through functional magnetic resonance imaging (fMRI) in relation to the OPRM1 polymorphism. FM patients required lower pressure pain-inducing stimuli than healthy controls to achieve similar pain intensities, indicating heightened pain sensitivity. We found that OPRM1 G-genotype carriers showed increased activation in pain-related brain regions such as the posterior cingulate cortex extending to the precentral gyrus, compared to AA homozygotes. In addition, seed-based functional connectivity analysis revealed that G-allele carriers had a decreased functional connectivity between the posterior cingulate cortex/precentral gyrus and prefrontal cortex. Our results show that the OPRM1 G-genotype is associated with altered central pain processing, but it remains to be resolved whether this is more pronounced in FM or a generalized finding.

The final study, Study IV, investigated the relationship between several polymorphisms including a translocator protein (TSPO) gene polymorphism, TSPO being a marker of neuroinflammation, and levels of anti-satellite glia cell antibodies (anti-SGC IgG) in FM patients. Anti-SGC IgG target satellite glia cells (SGC), cells important for neuron-immune cell interaction. The main finding was that the TSPO polymorphism was associated with increased anti-SGC IgG levels, particularly in individuals with the high-affinity binding (HAB) genotype. This study suggests a novel link between TSPO-mediated immune processes and the pathophysiology of FM, highlighting the role of peripheral immune mechanisms in FM.

In conclusion, studies I-III identifies genetic polymorphisms in genes coding for major opioid and serotonergic receptors/transporters that influence pain processing and modulation. The findings provide insight into the underlying genetic factors that contribute to the variability in pain modulation in humans, but do not seem to be specifically associated with the dysfunction of endogenous pain modulation in FM. Study IV indicates that genetic factors influence autoimmune mechanisms and may partly explain the great variation of anti-SGC IgG within the FM population. The results presented in this thesis underscore the importance of considering both central and peripheral pain mechanisms in FM pathophysiology. Also, the importance of the interaction between neurophysiological and neuroimmune mechanisms has just started to be elucidated in FM, and further research in this field will certainly provide more understanding of the pathophysiology of FM.

List of scientific papers

I. Tour J, Löfgren M, Mannerkorpi K, Gerdle B, Larsson A, Palstam A, Bileviciute-Ljungar I, Bjersing J, Martin I, Ernberg M, Schalling M, Kosek E. Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes. Pain, 2017; 158(7), 1194- 1203.
https://doi.org/10.1097/j.pain.0000000000000896

II. Tour J, Sandström A, Kadetoff D, Schalling M, Kosek E. The OPRM1 gene and interactions with the 5-HT1a gene regulate conditioned pain modulation in fibromyalgia patients and healthy controls. PLOS ONE, 2022; 17(11): e0277427.
https://doi.org/10.1371/journal.pone.0277427

III. Ellerbrock I, Sandström A, Tour J, Kadetoff D, Schalling M, Jensen KB, Kosek E. Polymorphisms of the u-opioid receptor gene influence cerebral pain processing in fibromyalgia. European Journal of Pain, 2021; 25(2), 398-414.
https://doi.org/10.1002/ejp.1680

IV. Tour Sohlin J, Andersson S, Menezes J, Sandström A, Kadetoff D, Krock E, Hunt MA, Schalling M, Sandor K, Svensson C, Kosek E. Genetic polymorphisms associated with autoimmune mechanisms in fibromyalgia patients. [Manuscript]