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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]