Kappa opioid receptor-dependent depressive-like behaviors associated with morphine withdrawal contribute to stress-induced reinstatement of morphine seeking.

Negative effects during withdrawal heighten vulnerability to relapse in clinical settings. However, preclinical evidence linking withdrawal-induced negative emotions to relapse vulnerability remains limited. Previously, we have demonstrated that kappa opioid receptor (KORs) activation in the amygdala and subsequent inhibition of the amygdala-to-nucleus accumbens circuit mediate morphine withdrawal-induced depressive-like behaviors. In this study, we established a positive correlation between withdrawal-induced depressive-like behavior and stress-induced reinstatement in male mice. We found that morphine-treated mice displaying higher conditioned place preference (CPP) scores also exhibited more severe depressive-like behaviors during withdrawal and subsequently showed more pronounced CPP reinstatement following forced swim stress (FSS). We further found that inhibition of KOR activation in the basolateral amygdala (BLA), or activation of the BLA-NAc circuit, attenuated withdrawal-induced depressive-like behaviors and prevented subsequent stress-induced CPP reinstatement. Conversely, overexpression of KORs in the BLA-NAc circuit exacerbated these phenotypes, while genetic ablation of KORs in this circuit provided protective effects against these behaviors. Moreover, we identified a specific population of prelimbic cortex prodynorphinergic (PrLPdyn) neurons projecting to the BLA that are activated during both morphine withdrawal and FSS. Inhibition of these BLA-projecting PrLPdyn neurons alleviated morphine withdrawal-induced depressive-like behaviors and blocked stress-induced CPP reinstatement. Collectively, these findings support the idea that negative affective states during opioid withdrawal may drive relapse vulnerability, and the dynorphin/KOR system represents a critical therapeutic target for reducing negative effects and preventing relapse.