Department of Psychology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Center for Addiction and Pain Prevention and Intervention (CAPPI), University of Alabama at Birmingham, Birmingham, AL, USA.
Clin Epigenetics. 2022 Mar 26;14(1):45. doi: 10.1186/s13148-022-01265-z.
The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP.
In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM.
Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group.
This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP.
高达 90%的慢性下背痛（CLBP）患者无法确定其病理解剖原因。然而，内源性伤害性传入的功能失调处理，以条件疼痛调制（CPM）来衡量，与 CLBP 有关，并且可能涉及神经元基因表达的变化。DNA 甲基化（DNAm）等表观遗传诱导的变化与 CLBP 有关。
本研究使用简化代表性亚硫酸盐测序，检查了社区居住的非特异性 CLBP 个体（n=48）和无疼痛对照者（PFC；n=50）样本中 CPM 与 DNAm 变化之间的关系。通过基因本体论（GO）术语富集和京都基因与基因组百科全书（KEGG）途径分析，确定了与有效和低效 CPM 相关的关键途径。
基于 CPM 效率，我们在 CLBP 患者和 PFCs 中分别鉴定出 6006 个和 18305 个具有 q 值<0.01 的差异甲基化 CpG 位点（DMCs）。大多数 DMCs呈低甲基化状态，并注释到与疼痛相关的基因，包括 OPRM1、ADRB2、CACNA2D3、GNA12、LPL、NAXD 和 ASPHD1。在 CLBP 和 PFC 组中，DMC 注释的基因富集了许多与疼痛处理相关的 GO 术语，包括 RNA 聚合酶 II 的转录调节、神经系统发育、神经元生成、神经元分化和神经发生。两组均富集了参与 Rap1 信号、癌症和多巴胺能神经发生的途径。然而，MAPK-Ras 信号通路仅在 CLBP 组中富集，而不在 PFC 组中富集。
这是第一项研究，探讨了成人 CLBP 和 PFCs 中 CPM 表型的全基因组 DNA 甲基化谱。基于 CPM 效率，CLBP 组中独特的 DMC 富集途径少于 PFC 组。我们的结果表明，神经元发育/分化途径的表观遗传诱导修饰可能会影响 CPM 效率，为中枢敏化提供新的潜在治疗靶点。然而，CPM 效率和非特异性 CLBP 的体验可能是独立的。需要进一步的机制研究来确认 CPM、中枢敏化和非特异性 CLBP 之间的关系。
