Good news! Are we coming closer to better or alternative treatment options?
"Although the immune system has long been implicated in opioid withdrawal, the new findings ... are the first to link the immune system’s interactions with the central nervous system and especially the blood-brain barrier to withdrawal ...
“The work represents a major advance in the emerging field of neural-immune interactions and the role of immune cells and mediators in modulating neural processes during opioid exposure,” ...
In the study, the researchers examined the blood of 21 human heroin users and compared it to that of 20 controls, finding that the former group’s blood contained various biomarkers suggesting their immune systems were in disarray ... Investigating further with a series of flow cytometry experiments, they found that the heroin-using group’s blood contained high levels of an unusual immune cell called fragile-like regulatory T cells (Tregs). Tregs are usually involved in immunosuppression, but ones in this fragile-like state—which had previously only been observed in tumor microenvironments—lose their suppressive functions and instead produce the inflammatory cytokine interferon-γ (IFN-γ). The study authors write that opioid-induced hypoxia may have caused the cells’ unexpected state, as hypoxia has been implicated in triggering fragile-like states in the Tregs near tumors. ...
Analysis of samples taken from the heroin-treated mice revealed that IFN-γ was not only more prevalent in the bloodstream, but also in the nucleus accumbens, a brain region that modulates goal-directed behaviors and reward pathways, making it relevant to understanding and treating addiction. ...
In both IFN-γ knockout mice and mice treated with an IFN-γ-neutralizing antibody prior to opioid treatment, neural connections remained strong and unchanged throughout withdrawal even though the fragile-like Treg cells still infiltrated the brain. In these experiments, mice displayed reduced and shorter-lived withdrawal symptoms—in one case for just 12 hours instead of 60. ..."
“The work represents a major advance in the emerging field of neural-immune interactions and the role of immune cells and mediators in modulating neural processes during opioid exposure,” ...
In the study, the researchers examined the blood of 21 human heroin users and compared it to that of 20 controls, finding that the former group’s blood contained various biomarkers suggesting their immune systems were in disarray ... Investigating further with a series of flow cytometry experiments, they found that the heroin-using group’s blood contained high levels of an unusual immune cell called fragile-like regulatory T cells (Tregs). Tregs are usually involved in immunosuppression, but ones in this fragile-like state—which had previously only been observed in tumor microenvironments—lose their suppressive functions and instead produce the inflammatory cytokine interferon-γ (IFN-γ). The study authors write that opioid-induced hypoxia may have caused the cells’ unexpected state, as hypoxia has been implicated in triggering fragile-like states in the Tregs near tumors. ...
Analysis of samples taken from the heroin-treated mice revealed that IFN-γ was not only more prevalent in the bloodstream, but also in the nucleus accumbens, a brain region that modulates goal-directed behaviors and reward pathways, making it relevant to understanding and treating addiction. ...
In both IFN-γ knockout mice and mice treated with an IFN-γ-neutralizing antibody prior to opioid treatment, neural connections remained strong and unchanged throughout withdrawal even though the fragile-like Treg cells still infiltrated the brain. In these experiments, mice displayed reduced and shorter-lived withdrawal symptoms—in one case for just 12 hours instead of 60. ..."
From the highlights and abstract:
"Highlights
• An expansion of fragile-like Tregs is identified in heroin-associated blood
• Opioid-induced global hypoxia triggers Treg fragility
• Fabp7 protects BBB integrity from opioid-induced hyperpermeability
• IFN-γ regulates opioid-induced NAc synaptic remodeling and withdrawal signs
Summary
Dysregulation of the immune system is a cardinal feature of opioid addiction. Here, we characterize the landscape of peripheral immune cells from patients with opioid use disorder and from healthy controls. Opioid-associated blood exhibited an abnormal distribution of immune cells characterized by a significant expansion of fragile-like regulatory T cells (Tregs), which was positively correlated with the withdrawal score. Analogously, opioid-treated mice also showed enhanced Treg-derived interferon-γ (IFN-γ) expression. IFN-γ signaling reshaped synaptic morphology in nucleus accumbens (NAc) neurons, modulating subsequent withdrawal symptoms. We demonstrate that opioids increase the expression of neuron-derived C-C motif chemokine ligand 2 (Ccl2) and disrupted blood-brain barrier (BBB) integrity through the downregulation of astrocyte-derived fatty-acid-binding protein 7 (Fabp7), which both triggered peripheral Treg infiltration into NAc. Our study demonstrates that opioids drive the expansion of fragile-like Tregs and favor peripheral Treg diapedesis across the BBB, which leads to IFN-γ-mediated synaptic instability and subsequent withdrawal symptoms."
Graphical abstract
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