The impact of chronic pain on brain gene expression

Abstract

Chronic pain affects one-fifth of American adults, contributing significant public health burden. Chronic pain can be further understood through investigating brain gene expression, potentially informing on brain regions, cell types, and gene pathways. We tested for differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in 4 brain regions (dorsal anterior cingulate cortex [dACC], dorsolateral prefrontal cortex [DLPFC], medial amygdala [MeA], and basolateral amygdala [BLA]) and imputed cell type expression data from 304 deeply phenotyped postmortem donors, potentially highlighting variation relevant to factors such as predisposition to chronic pain development, mechanisms of chronic pain development and persistence, and indirect effects of chronic pain and associated treatment or medication, and substance use. We also investigated sex differences in chronic pain differential gene expression. At the brain region level, we identified 2 chronic pain DEGs: B4GALT2 and VEGFB in dACC. At the cell level, we found more than 2000 chronic pain cell-type DEGs, significantly enriched in microglia of the basolateral amygdala. The findings were enriched for mouse microglia pain genes, and for hypoxia and immune response pathways. Small amounts of cross-trait DEG overlap in migraine and chronic pain highlighted medial amygdala cells, and in chronic pain and oxymorphone use suggested the amygdala as a key region. Chronic pain differential gene expression was not significantly different between men and women. Overall, chronic pain-associated gene expression is heterogeneous across region and cell type, is largely distinct from that in pain-related factors and migraine, and our results highlight BLA microglia as a key brain cell type in chronic pain.

Keywords: Amygdala; Chronic pain; Cortex; Differentially expressed genes; Microglia; Opioids; Polygenic risk scores; Postmortem brain donors; Transcriptomics.

Figure 1.

Chronic pain DEGs are found in the dACC and in the microglia of the basolateral amygdala in bulk and cell type-level analyses. (A) Bulk tissue chronic pain DEGs. Purple: significantly (P_Bonferroni < 0.05) downregulated; dotted line = DEG regression P value significance threshold for that bulk region. (B) Imputed cell-type proportions vary across bulk regions—note neurons only present in reference data for cortex (PsychENCODE) and oligodendrocyte progenitor cells (OPCs) only present in amygdala reference data (Yu et al); OPCs and Neurons both marked “Other” in this figure. (C) Chronic pain cell-type DEGs in microglia per region. Purple = significantly (P_Bonferroni < 0.05) downregulated, orange = significantly (P_Bonferroni < 0.05) upregulated, dotted line = P value significance threshold. For legibility, only the top 15 DEGs are labeled in cell type results panel. dACC, dorsal anterior cingulate cortex; DEG, differentially expressed gene; E × N, excitatory neuron; FC, fold change; InN, inhibitory neuron.

Figure 2.

Cell-type DEG overlap across all traits (lifetime oxymorphone use, lifetime fentanyl use, multisite chronic pain PRS, chronic pain, and migraine) tends to be low. DEG, differentially expressed gene; MCP-PRS, multisite chronic pain-polygenic risk score.