Summary: Inflammation in both the brain and the gut triggered by opioid use may intensify the negative emotional symptoms of withdrawal. Reducing this inflammation could help ease withdrawal-related distress and lower the risk of continued dependence.
Source: Thomas Jefferson University
Overview: Opioid dependence remains a widespread public health crisis with far-reaching social and economic consequences. One of the major drivers of continued opioid use is the severe physical and emotional distress that accompanies withdrawal. These aversive withdrawal symptoms frequently motivate ongoing drug use and present a substantial obstacle to recovery.
Researchers in the laboratory of James Schwaber at the Daniel Baugh Institute for Functional Genomics and Computational Biology, Thomas Jefferson University, examined how inflammation contributes to withdrawal and to the persistence of opioid dependence. Their results were published in Frontiers in Neuroscience on July 3.
Opioids can provoke inflammatory signaling in the brain by activating resident immune cells, which then release pro-inflammatory molecules known as cytokines. The brain’s principal immune cells, microglia and astrocytes, are central to these responses. Prior work has identified opioid-induced inflammatory changes in the central amygdala, a brain region strongly implicated in the emotional and motivational components of dependence. The central amygdala is also sensitive to signals from peripheral inflammation, including inflammatory processes originating in the gut. Emerging evidence indicates that gut–brain communication influences motivated behaviors and emotional states, and therefore may shape responses to drugs and withdrawal.
In this study, first author Sean O’Sullivan and colleagues used single-cell isolation to capture individual neurons, microglia, and astrocytes from the central amygdala of control, opioid-dependent, and withdrawn rats. They profiled gene expression in each cell type to determine how cellular transcriptional programs change with dependence and withdrawal. The most pronounced transcriptional shift occurred in astrocytes, which adopted a more activated, inflammatory state during withdrawal. All three cell types—neurons, microglia, and astrocytes—showed increased expression of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) in withdrawn animals.
Alongside the brain cell analyses, the team profiled gut microbiota in the same groups of rats. They observed reductions in certain bacteria associated with anti-inflammatory effects and a changed balance between major bacterial groups, a condition known as gut dysbiosis. The shift in microbial composition during withdrawal suggests increased potential for peripheral inflammation in the digestive system.
Although the precise causal links between gut microbiota changes and brain inflammation remain to be fully established, the investigators propose that simultaneous inflammatory changes in the gut and in the central amygdala may interact to amplify the negative emotional experience of opioid withdrawal. In other words, gut dysbiosis and central nervous system inflammation may form a bidirectional loop that worsens withdrawal symptoms and thereby reinforces drug-seeking behavior.
These findings highlight the complex interplay between peripheral and central inflammatory processes in the context of opioid withdrawal. By identifying astrocyte activation and elevated TNF-α expression in the central amygdala, together with concurrent gut microbiota alterations, the study points to inflammation as a potential therapeutic target. Interventions that reduce inflammation—whether acting in the brain, the gut, or both—might lessen the intensity of withdrawal-related negative emotions and make recovery from dependence more attainable.
Methods and interpretation: The investigators used laser capture microdissection to obtain single cells from the central amygdala, followed by gene expression analysis to detect cell type–specific inflammatory signatures. Gut bacterial communities were characterized to evaluate changes in microbial balance associated with dependence and withdrawal. The combined single-cell and gut microbiome approach provides a more integrated view of how neuroinflammation and peripheral microbiota shifts may jointly contribute to the affective components of opioid withdrawal.
Funding: This research was supported by NIH HLB U01 HL133360, NIDA R21 DA036372, and T32 AA-007463. The authors report no conflicts of interest.
Source:
Thomas Jefferson University
Media contact:
Karuna S Meda – Thomas Jefferson University
Image source:
The image is in the public domain.
Original research (open access):
“Single-Cell Glia and Neuron Gene Expression in the Central Amygdala in Opioid Withdrawal Suggests Inflammation With Correlated Gut Dysbiosis”, Sean O’Sullivan et al., Frontiers in Neuroscience. doi: 10.3389/fnins.2019.00665
Abstract (summary): The authors measured single-cell gene expression in glia and neurons from the central amygdala and simultaneously profiled gut microflora in morphine-dependent and withdrawn rats. They observed upregulation of neuroinflammatory genes—most notably Tnf—during withdrawal, marked activation of astrocytes, and a decreased Firmicutes-to-Bacteroides ratio indicating gut dysbiosis. These coordinated changes in brain inflammation and gut microbiota may underlie the negative emotional states that drive opioid-seeking behavior during withdrawal.