Gombert Sara, Rhein Mathias, Eberhardt Mirjam, Münster Tino, Bleich Stefan, Leffler Andreas, Frieling Helge
Laboratory for Molecular Neuroscience, Department of Psychiatry, Socialpsychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany.
Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Hannover, Germany.
Pain. 2017 Apr;158(4):698-704. doi: 10.1097/j.pain.0000000000000815.
The expression pattern of important transduction molecules in nociceptive sensory neurons is likely to dictate pain sensitivity. While this notion is well established for increased pain sensitivities under conditions like inflammation and neuropathy, less is known as to which molecules are defining interindividual differences in pain sensitivity in healthy subjects. A genome-wide methylation analysis on monozygotic twins found that methylation of a CpG dinucleotide in the promoter of transient receptor potential ankyrin 1 (TRPA1) is inversely associated with the threshold for heat-induced pain. Several in vitro studies also suggest that TRPA1 mediates mechanical sensitivity of sensory afferents, thus potentially mediating pressure-evoked pain. In the present study, we therefore investigated the epigenetic predisposition for pressure pain by analyzing the methylation status of 47 CpG sites in the promoter region of TRPA1. Using DNA from whole-blood samples of 75 healthy volunteers, we found that the same CpG site previously found to affect the threshold for heat-evoked pain is hypermethylated in subjects with a low threshold for pressure pain. We also found gender differences, with females displaying higher methylation rates combined with higher pressure pain sensitivities as compared with males. In conclusion, our findings support the notion that epigenetic regulation of TRPA1 seems to regulate thermal and mechanical pain sensitivities.
伤害性感觉神经元中重要转导分子的表达模式可能决定疼痛敏感性。虽然在炎症和神经病变等情况下疼痛敏感性增加这一观点已得到充分证实，但对于哪些分子决定健康受试者疼痛敏感性的个体差异却知之甚少。一项对同卵双胞胎的全基因组甲基化分析发现，瞬时受体电位锚蛋白1（TRPA1）启动子中一个CpG二核苷酸的甲基化与热诱导疼痛阈值呈负相关。多项体外研究还表明，TRPA1介导感觉传入神经的机械敏感性，因此可能介导压力诱发的疼痛。因此，在本研究中，我们通过分析TRPA1启动子区域47个CpG位点的甲基化状态，研究了压力疼痛的表观遗传易感性。利用75名健康志愿者全血样本中的DNA，我们发现，之前发现影响热诱发疼痛阈值的同一个CpG位点，在压力疼痛阈值较低的受试者中甲基化程度较高。我们还发现了性别差异，与男性相比，女性表现出更高的甲基化率以及更高的压力疼痛敏感性。总之，我们的研究结果支持这样一种观点，即TRPA1的表观遗传调控似乎调节热痛和机械性疼痛敏感性。
