A prefrontal peptidergic circuit for psychogenic itch

Psychological stress can evoke itch without a peripheral stimulus, yet the underlying mechanism remains undefined. Here, we demonstrate that a peptidergic circuit within the medial prefrontal cortex (mPFC) mediates this phenomenon. In mice under chronic restraint stress, stress-elicited scratching coincided with elevated gastrin-releasing peptide (GRP) release and heightened activity of GRP receptor (GRPR)–expressing neurons in the mPFC. Microinjection of GRP into the mPFC reproduced stress-induced itch, whereas ablation of GRPR neurons abolished it. Optogenetic activation of GRPR neurons or their GRP-expressing inputs from the ventromedial thalamus and basolateral amygdala evoked robust scratching; conversely, silencing these inputs or GRPR neurons attenuated scratching. Collectively, our findings establish a central peptidergic mechanism that transduces psychological stress into pruriceptive output, thereby identifying a critical neural substrate for psychogenic itch.