Good news! Will we finally be able to defeat or treat withdrawal symptoms?
"... Although the immune system has long been implicated in opioid withdrawal, the new findings, published January 19 in Cell, 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,” ...
With the mechanism pieced together, the researchers also showed that they could break it down, at least in mice. In both IFN-γ knockout mice and mice treated with an IFN-γ-neutralizing antibody prior to opioid treatment, neural connects 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,” ...
With the mechanism pieced together, the researchers also showed that they could break it down, at least in mice. In both IFN-γ knockout mice and mice treated with an IFN-γ-neutralizing antibody prior to opioid treatment, neural connects 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."
Opioid-induced fragile-like regulatory T cells contribute to withdrawal (no public access)
Graphical abstract
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