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.
Department of Clinical Neuroscience and Osher Center, Karolinska Insitutet, Department of Neuroradiology, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
Brain Behav Immun. 2016 Nov;58:218-227. doi: 10.1016/j.bbi.2016.07.150. Epub 2016 Jul 20.
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.
转位蛋白（TSPO）在慢性疼痛患者的神经胶质细胞激活过程中上调。TSPO 构成神经甾体合成的限速步骤，从而调节突触传递。相关的 5-羟色胺能机制影响是否产生促痛或抗痛神经甾体。本研究调查了调节与 TSPO 结合亲和力的功能遗传多态性对纤维肌痛患者症状严重程度和大脑疼痛处理的影响。评估了与 5-羟色胺转运体基因的功能多态性的基因-基因相互作用。对纤维肌痛患者（n=126）进行 TSPO（rs6971）和 5-羟色胺转运体（5-HTTLPR/rs25531）多态性的基因分型。使用功能磁共振成像（n=24）研究个体校准压力疼痛期间的大脑激活。与混合/低 TSPO 亲和力结合物相比，高 TSPO 亲和力结合物的疼痛评分更高（p=0.016）和纤维肌痛症状更严重（p=0.02）。在 TSPO 和 5-羟色胺转运体多态性之间发现了与疼痛严重程度显著的相互作用（p<0.0001）。功能连接分析表明，在右额顶网络中，TSPO 高亲和力结合组在背外侧前额叶区域和顶叶皮层之间具有更明显的疼痛诱发功能连接。总之，与混合/低亲和力结合物相比，TSPO 高亲和力结合基因型的纤维肌痛患者报告的疼痛强度更高，纤维肌痛症状更严重，这是由与 5-羟色胺转运体基因的相互作用调节的。据我们所知，这是第一个证明功能遗传多态性影响 FM 中疼痛严重程度的证据，我们的研究结果与提出的胶质细胞相关机制一致。此外，功能磁共振成像的发现表明转位蛋白对疼痛感知的情感-动机成分有影响。
