Summary: Neuroinflammation appears to be a central driver of the pathological brain changes associated with chronic opioid use, with microglia identified as a likely key cellular mediator.
Source: Boston University School of Medicine
Opioid use disorder (OUD) rates and opioid-related overdose deaths have risen sharply in recent years, highlighting an urgent need to understand how chronic opioid exposure alters the human brain. Although preclinical models have provided important insights, the specific molecular and cellular changes in the brains of people with OUD remain incompletely characterized.
To address this gap, researchers at Boston University School of Medicine conducted the largest transcriptomic analysis to date of postmortem brain tissue from individuals diagnosed with OUD. Using comprehensive RNA sequencing and computational analyses, the team examined gene expression changes in two brain regions tightly linked to addiction and decision-making: the dorsolateral prefrontal cortex (DLPFC) and the nucleus accumbens (NAc).
The analyses revealed coordinated transcriptional alterations in both the DLPFC and NAc that implicate inflammatory signaling and synaptic remodeling as prominent features of OUD. Many of the differentially expressed genes are involved in pro-inflammatory cytokine pathways, extracellular matrix and chondroitin sulfate signaling, and processes that shape synaptic structure and plasticity.
Importantly, cell-type deconvolution methods pointed to microglia—the brain’s resident immune cells—as a major contributor to these changes. The findings suggest that chronic opioid exposure engages immune-related pathways in the brain, which in turn may influence synaptic function and neural circuitry involved in cognition, impulsivity, risk-taking, and addictive behavior.
“Our results reveal a mechanism by which opioids may reconfigure brain circuits: activation of specific inflammatory pathways and microglial responses that alter synaptic plasticity,” said corresponding author Ryan W. Logan, PhD, associate professor of pharmacology & experimental therapeutics at Boston University School of Medicine. These molecular signatures provide a clearer picture of how opioid dependence affects human brain biology and identify potential targets for therapeutic intervention.
The study combined differential gene expression analyses with rank-rank hypergeometric overlap (RRHO) to assess transcriptional coherence between DLPFC and NAc, and used weighted gene co-expression network analysis (WGCNA) to define OUD-specific gene modules and networks. Integrative approaches compared transcriptomic results with genetic data to explore links between OUD-related expression patterns and genetic liability for psychiatric traits, including risky behavior, attention deficit hyperactivity disorder, and depression.
Overall, the data demonstrate extensive overlap in altered gene expression between the two regions, with shared signatures pointing to synaptic remodeling and neuroinflammatory processes as central themes. These results support a model in which microglial activation and extracellular matrix remodeling contribute to the neural circuit dysfunction observed in chronic opioid use.
Given the established association between neuroinflammation and a range of psychiatric and neurodegenerative conditions, these findings broaden our understanding of how inflammation may shape cognitive and behavioral outcomes in OUD. By identifying specific inflammatory pathways and cellular players, the study creates avenues for future research into targeted therapies that modulate neuroimmune signaling to restore synaptic function and reduce addiction-related behaviors.
This work was published in the journal Biological Psychiatry and represents an important step toward translating transcriptomic discoveries into clinical strategies for people living with opioid dependence.
Funding: Research support was provided by the Hamilton Family Prize for Basic Neuroscience Research in Psychiatry at the University of Pittsburgh School of Medicine, NHLBI R01HL150432, and NIDA R01DA051390.
About this opioid use disorder research news
Source: Boston University School of Medicine
Contact: Gina DiGravio – Boston University School of Medicine
Image: The image is in the public domain
Original Research: Open access. “Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder” by Ryan W. Logan et al., Biological Psychiatry
Abstract
Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder
Background
Opioid use disorder (OUD) prevalence and opioid-related fatalities have increased substantially. Although animal models have informed mechanisms of dependence, there is limited direct evidence of the molecular alterations in human brain tissue resulting from chronic opioid exposure. To address this, RNA sequencing (RNA-seq) was performed on postmortem dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc) samples from subjects diagnosed with OUD and unaffected comparison subjects.
Methods
RNA-seq was conducted on DLPFC and NAc tissue from unaffected comparison subjects (n=20) and subjects with OUD (n=20). Differentially expressed transcripts were identified and cross-region transcriptional coherence was evaluated using rank-rank hypergeometric ordering (RRHO). Weighted gene co-expression network analysis (WGCNA) identified OUD-specific gene modules. Integration with genome-wide association study (GWAS) data via linkage disequilibrium score regression assessed genetic liabilities related to psychiatric phenotypes.
Results
RRHO analyses demonstrated broad overlap in altered transcripts between DLPFC and NAc in OUD, particularly genes associated with synaptic remodeling and neuroinflammation. Enriched pathways included pro-inflammatory cytokine signaling, chondroitin sulfate and extracellular matrix processes. Cell-type deconvolution implicated microglia as a potential driver of opioid-induced neuroplastic changes. Integrative genetic analyses suggested shared liability with traits such as risky behavior, attention deficit hyperactivity disorder, and depression.
Conclusions
Collectively, these findings connect immune-related processes in the brain with opioid dependence and point to neuroinflammation and synaptic remodeling as central mechanisms in the human brain affected by chronic opioid use.