The impact of chronic pain on brain gene expression

Lily Collier; Carina Seah; Emily M Hicks; Paul E Holtzheimer; John H Krystal; Matthew J Girgenti; Laura M Huckins; Keira J A Johnston; Members of the Traumatic Stress Brain Research Group (Consortia Authors)

doi:10.1097/j.pain.0000000000003707

The impact of chronic pain on brain gene expression

Pain. 2025 Jul 7:10.1097/j.pain.0000000000003707. doi: 10.1097/j.pain.0000000000003707. Online ahead of print.

Collaborators

Members of the Traumatic Stress Brain Research Group (Consortia Authors):
Victor E Alvarez, David Benedek, Alicia Che, Dianne A Cruz, David A Davis, Matthew J Girgenti, Ellen Hoffman, Paul E Holtzheimer, Bertrand R Huber, Alfred Kaye, John H Krystal, Adam T Labadorf, Terence M Keane, Mark W Logue, Ann McKee, Brian Marx, Mark W Miller, Crystal Noller, Janitza Montalvo-Ortiz, Meghan Pierce, William K Scott, Paula Schnurr, Krista DiSano, Thor Stein, Robert Ursano, Douglas E Williamson, Erika J Wolf, Keith A Young

Affiliations

¹ Department of Biological Sciences, Columbia University, New York City, NY, United States.
² Division of Molecular Psychiatry, Department of Psychiatry, Yale University, New Haven, CT, United States.
³ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, United States.
⁴ U.S. Department of Veterans Affairs, National Center for PTSD, White River Junction, VT, United States.
⁵ Department of Psychiatry, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States.
⁶ Clinical Neuroscience Division, National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, United States.

PMID: 40623285
PMCID: PMC12236435 (available on 2026-07-07)
DOI: 10.1097/j.pain.0000000000003707

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.

Abstract

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