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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. [Display omitted] • 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 Opioids drive the peripheral expansion of fragile-like regulatory T cells that cross the blood-brain barrier and, through IFN-γ, mediate synaptic instability and subsequent withdrawal symptoms. [ABSTRACT FROM AUTHOR]

Opioid withdrawal generates extremely unpleasant physical symptoms and negative affective states. A rapid relief of opioid withdrawal-induced anxiety has obvious clinical relevance but has been rarely reported. We have shown that injection of ketamine metabolite (2 R ,6 R)-hydroxynorketamine (HNK) leads to a rapid alleviation of anxiety-like behaviors in male mice undergoing chronic morphine withdrawal. Here we investigated the contribution of nucleus accumbens shell (sNAc) parvalbumin (PV)-neurons to this process. Chronic morphine withdrawal was associated with higher intrinsic excitability of sNAc PV-neurons via reduced voltage-dependent potassium currents. Chemogenetic inhibition of sNAc PV-neurons reversed the enhanced excitability of PV-neurons and anxiety-like behaviors in these morphine withdrawal male mice, while activation of sNAc PV-neurons induced anxiety-like behaviors in naive male mice. (2 R ,6 R)-HNK reversed the altered potassium currents and intrinsic excitability of sNAc PV-neurons. Our findings demonstrate an important contribution of sNAc PV-neurons to modulating morphine withdrawal-induced anxiety-like behaviors and rapid relief of anxiety-like behaviors by (2 R ,6 R)-HNK, this newly identified target may have therapeutic potentials in treating opioid addiction and anxiety disorders. • sNAc PV-neuron excitability is higher in mice undergoing morphine withdrawal. • Inhibiting sNAc PV-neurons improves morphine withdrawal-induced anxiety-like behaviors. • Activating sNAc PV-neurons elicits anxiety-like behaviors in naïve mice. • (2 R ,6 R)-HNK alleviates morphine withdrawal-induced anxiety-like behaviors in mice. • (2 R ,6 R)-HNK increases K+ currents and reduces excitability of sNAc PV-neurons. [ABSTRACT FROM AUTHOR]