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.

J.H.K. has consulting agreements (less than US$10,000 per year) with the following: Aptinyx, Inc. Biogen, Idec, MA, Bionomics, Limited (Australia), Boehringer Ingelheim International, Epiodyne, Inc., EpiVario, Inc., Janssen Research & Development, Jazz Pharmaceuticals, Inc., Otsuka America Pharmaceutical, Inc., Spring Care, Inc., Sunovion Pharmaceuticals, Inc.; is the co-founder for Freedom Biosciences, Inc.; serves on the scientific advisory boards of Biohaven Pharmaceuticals, BioXcel Therapeutics, Inc. (Clinical Advisory Board), Cerevel Therapeutics, LLC, Delix Therapeutics, Inc., Eisai, Inc., EpiVario, Inc., Jazz Pharmaceuticals, Inc., Neumora Therapeutics, Inc., Neurocrine Biosciences, Inc., Novartis Pharmaceuticals Corporation, PsychoGenics, Inc., Takeda Pharmaceuticals, Tempero Bio, Inc., Terran Biosciences, Inc..; has stock options with Biohaven Pharmaceuticals Medical Sciences, Cartego Therapeutics, Damona Pharmaceuticals, Delix Therapeutics, EpiVario, Inc., Neumora Therapeutics, Inc., Rest Therapeutics, Tempero Bio, Inc., Terran Biosciences, Inc., Tetricus, Inc.; and is editor of Biological Psychiatry with income greater than $10,000

LMH acknowledges funding from NIMH (R01MH124839, R01MH118278, R01MH125938, RM1MH132648, R01MH136149), NIEHS (R01ES033630), and the Department of Defense (TP220451). JHK acknowledges support from the Clinical Neuroscience Division of the National Center for PTSD (Department of Veterans Affairs). CS acknowledges funding from NIH (F30MH132324).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethical approval associated with VA Biorepository Brain Bank: The National PTSD Brain Bank/ IRB 32887/ IRBNet ID 1578200. Consent was provided by next of kin at time of brain donation. We also note the research in our study is not human subjects research under HHS 45 CFR part 46, a human subject is defined as a living individual about whom an investigator conducting research obtains data through intervention or interaction with the individual or identifiable private information.This research involved the analysis of gene expression (RNA) data, along with associated phenotype, and genotype data, from postmortem human brain tissue.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Full summary data from DEG analyses results is available upon reasonable request to the authors. Requests for access to raw and processed genotype, gene expression, and phenotype data can be made by researchers to the VA National PTSD Brain Bank https://www.research.va.gov/programs/tissue_banking/PTSD/default.cfm