Jing-Gen Liu

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 (PrL^Pdyn) neurons projecting to the BLA that are activated during both morphine withdrawal and FSS. Inhibition of these BLA-projecting PrL^Pdyn 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.

Itch, an uncomfortable sensation that induces scratching, is suppressed by activation of kappa opioid receptors (KORs). KOR agonists, such as Nalfurafine, offer potent central antipruritic effects, yet the underlying mechanisms are not fully understood. In this study, we report the important role of glutamatergic neurons in the claustrum (CLA) in itch modulation. Chemogenetic inhibition of these neurons significantly reduces histamine-induced scratching behavior, whereas their activation heightens scratching behavior. These CLA ^Glu neurons connect to the mediodorsal thalamus (MD), forming a pathway that modulates itch sensations. Optogenetic manipulation of the CLA ^Glu -MD pathway demonstrates that its inhibition decreases scratching behavior, whereas activation increases it. Notably, CLA ^Glu neurons highly express KORs, and treatment with Nalfurafine markedly inhibits histamine-induced CLA ^Glu neuronal activation. Conditional knockdown of KORs in CLA ^Glu neurons or the CLA ^Glu -MD circuit diminishes Nalfurafine’s antipruritic effects. These findings provide insight into the neural circuits involved in histaminergic itch and the action of KOR agonists.

Multiple lines of evidence, including clinical and preclinical, associate depression with dysregulated glutamate homeostasis in the central nervous system. The astrocyte-enriched cysteine/glutamate antiporter, xCT, plays a pivotal role in maintaining this homeostasis, and its dysfunction is linked to depressive-like behaviors induced by chronic stress. However, the exact mechanism through which chronic stress results in xCT dysfunction remains poorly understood. In this study, we demonstrate that chronic social defeat stress (CSDS) downregulates xCT expression in the prelimbic cortex (PL), a key cortical region involved in the aetiology of depression, through astroglial kappa opioid receptor (KOR)-dependent, p38 MAPK-mediated upregulation of miR-3084-5p expression, which in turn downregulates xCT expression by inhibiting mRNA that encodes xCT. Knockdown of KORs as well as overexpression of xCT in the PL astrocytes significantly attenuates CSDS-induced depressive-like behaviors. Blockade of p38 MAPK activity or suppression of miR-3084-5p function restores xCT expression and alleviates depressive-like behaviors. Together, this study reveals a novel mechanism by which chronic stress deregulates glutamate homeostasis and consequently results in depression.