Differential regulation of pruritic sensation and emotion by cannabinoid type 1 receptors on mPFC glutamatergic and GABAergic neurons

Itch causes a strong urge to scratch and induces negative emotions, such as aversion and anxiety. Antihistamine medications are key in the clinical management of pruritus, but their therapeutic efficacy in controlling moderate and severe itching remains limited. The neural circuits in the brain that process itching and itch-induced aversion and anxiety remain unclear so far. Human brain imaging suggests that the medial prefrontal cortex (mPFC) is involved in processing the emotional and motivational components of itching. In this study, we investigated the mechanisms by which glutamatergic and GABAergic neurons in mPFC differentially regulated pruritic sensation and emotion through cannabinoid type 1 receptors (CB1Rs). Chloroquinoline (CQ)-induced acute and calcipotriol (MC903)-induced chronic itch models were established. Fiberoptic calcium imaging was used to detect the activity of the two types of neurons in response to itching. The CB1R antagonist AM251 (0.5 mg in 200 nL) was microinjected into the mPFC through the implanted cannula. We showed that chemogenetic activation of glutamatergic neurons and inhibition of GABAergic neurons in the mPFC reduced scratching and chronic itch-induced anxiety. GABAergic, but not glutamatergic, neurons were involved in acute itch-induced aversion. CB1Rs on glutamatergic and GABAergic neurons modulated chronic itch-induced scratching and anxiety in divergent manners. However, CB1Rs did not affect acute itch-induced scratching. CB1Rs on GABAergic, but not glutamatergic, neurons regulated acute itch-induced aversion. These results may guide the development of therapeutic strategies targeting CB1Rs to treat itch-induced sensory and emotional responses.