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[Preprint]. 2024 May 21:2024.05.20.24307630.
doi: 10.1101/2024.05.20.24307630.

The impact of chronic pain on brain gene expression

Lily Collier  1   2 , Carina Seah  3 , Emily M Hicks  3 ; Traumatic Stress Brain Research Group; Paul E Holtzheimer  4   5 , John H Krystal  2   6 , Matthew J Girgenti  2   6 , Laura M Huckins  2 , Keira J A Johnston  2
Affiliations

The impact of chronic pain on brain gene expression

Lily Collier et al. medRxiv. .

Update in

  • The impact of chronic pain on brain gene expression.
    Collier L, Seah C, Hicks EM, Holtzheimer PE, Krystal JH, Girgenti MJ, Huckins LM, Johnston KJA; Members of the Traumatic Stress Brain Research Group (Consortia Authors). Collier L, et al. Pain. 2025 Jul 7:10.1097/j.pain.0000000000003707. doi: 10.1097/j.pain.0000000000003707. Online ahead of print. Pain. 2025. PMID: 40623285

Abstract

Background: Chronic pain affects one fifth of American adults, contributing significant public health burden. Chronic pain mechanisms can be further understood through investigating brain gene expression.

Methods: We tested differentially expressed genes (DEGs) in chronic pain, migraine, lifetime fentanyl and oxymorphone use, and with chronic pain genetic risk in four brain regions (dACC, DLPFC, MeA, BLA) and imputed cell type expression data from 304 postmortem donors. We compared findings across traits and with independent transcriptomics resources, and performed gene-set enrichment.

Results: We identified two chronic pain DEGs: B4GALT and VEGFB in bulk dACC. We found over 2000 (primarily BLA microglia) chronic pain cell type DEGs. Findings were enriched for mouse microglia pain genes, and for hypoxia and immune response. Cross-trait DEG overlap was minimal.

Conclusions: Chronic pain-associated gene expression is heterogeneous across cell type, largely distinct from that in pain-related traits, and shows BLA microglia are a key cell type.

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Figures

Figure 1:
Figure 1:. Chronic pain DEGs are found in the dACC and in microglia of the basolateral amygdala in bulk and cell-type-level analyses.
1A: Bulk tissue chronic pain DEGs. Purple: significantly (PBonferroni < 0.05) downregulated, dotted line = DEG regression p value significance threshold for that bulk region. FC = fold change. 1B: 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 panel. FC = fold change. 1C: Chronic pain cell type DEGs in microglia per region. Purple = significantly (PBonferroni < 0.05) downregulated, orange = significantly (PBonferroni < 0.05) upregulated, dotted line = p value significance threshold. For legibility only the top 15 DEGs are labeled in cell type results panel. FC = fold change. InN = inhibitory neuron, ExN = excitatory neuron.
Figure 2:
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.
PRS – polygenic risk score (MCP-PRS).
See this image and copyright information in PMC

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