Summary: Neuroinflammation may be a key player in the pathological brain changes produced as a result of chronic opioid use. Microglia is likely responsible for the majority of the changes.
Source: Boston University School of Medicine
Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths–nearly 50,000 in the U.S. in 2019. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited.
To address this issue, researchers from Boston University School of Medicine (BUSM) have conducted the largest transcriptomic (the study of all the RNA molecules within a cell) study to date using postmortem brains from people with OUD.
Their findings for the first time show a critical role for neuroinflammation as the driver of the pathological brain alterations produced by chronic opioid use. They also identify microglia (the most prominent immune cells of the central nervous system and the first to respond when something goes wrong in the brain) as the cell type responsible for many of these changes.
“Our study has yielded a number of surprising and important findings, including how two of the most critical brain regions associated with opioid dependence, the prefrontal cortex and nucleus accumbens, communicate with one another under “healthy” conditions, as well as how opioids alter fundamental brain processes contributing to opioid dependence,” explained corresponding author Ryan W. Logan, PhD, associate professor of pharmacology & experimental therapeutics at BUSM.
To investigate the molecular changes in the human brain associated with opioid dependence, the researchers used transcriptomic and computational approaches to examine gene changes in the prefrontal cortex and nucleus accumbens and discovered changes associated with inflammation and synaptic structure/function in the brains of people who are diagnosed with OUD.
“The data reveals a new mechanism by which opioids may alter the brains’ structure to change synaptic plasticity, ultimately resulting in behavioral changes,” said Logan.
According to the researchers, inflammation in the brain is related to several psychiatric disorders and neurological disorders including neurodegeneration and aging-related brain diseases. “Our findings highlight the potential role for activation of specific inflammatory pathways in the brain and their interplay in brain processes related to cognition, impulsivity, risk-taking and substance use,” he added.
The researcher believe this this work offers a new context for neuroinflammatory actions in the human brain that may explain how opioids produce circuit dysfunction. In addition, it may provide new insights into potential targets for therapeutic development in treating people suffering with opioid dependence.
These finding appear online the journal Biological Psychiatry.
Funding: Funding for this study was provided by the Hamilton Family Prize for Basic Neuroscience Research in Psychiatry at the University of Pittsburgh School of Medicine to R.W.L., NHLBI R01HL150432 to R.W.L, and NIDA R01DA051390 to R.W.L and M.L.S.
Transcriptional alterations in dorsolateral prefrontal cortex and nucleus accumbens implicate neuroinflammation and synaptic remodeling in opioid use disorder
Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, an understanding of the biological alterations that occur in the brains of people who chronically use opioids and who are diagnosed with OUD remains limited. To address this limitation, RNA-sequencing (RNA-seq) was conducted on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), regions heavily implicated in OUD, from postmortem brains in subjects with OUD.
We performed RNA-seq on the DLPFC and NAc from unaffected comparison subjects (n=20) and subjects diagnosed with OUD (n=20). Our transcriptomic analyses identified differentially expressed (DE) transcripts and investigated the transcriptional coherence between brain regions using rank-rank hypergeometric ordering (RRHO). Weighted gene co-expression analyses (WGCNA) also identified OUD-specific modules and gene networks. Integrative analyses between DE transcripts and GWAS datasets using linkage disequilibrium score (LDSC) assessed the genetic liability psychiatric-related phenotypes.
RRHO analyses revealed extensive overlap in transcripts between DLPFC and NAc in OUD, primarily relating to synaptic remodeling and neuroinflammation. Identified transcripts were enriched for factors that control pro-inflammatory cytokine-mediated, chondroitin sulfate, and extracellular matrix signaling. Cell-type deconvolution implicated a role for microglia as a potential driver for opioid-induced neuroplasticity. LDSC analysis suggested genetic liabilities for risky behavior, attention deficit hyperactivity disorder, and depression in subjects with OUD.
Overall, our findings suggest connections between the brain’s immune system and opioid dependence in the human brain.