Cannabinoid CB₂ receptor controls chronic itch by regulating spinal microglial activation and synaptic transmission

Area of Science:

• Neuroimmunology
• Dermatology
• Pharmacology

Background:

• Chronic itch is a severe condition with poorly understood central mechanisms.
• Microglial activation in the spinal cord is implicated in the pathogenesis of chronic itch.
• Cannabinoid receptor type 2 (CB2R) has shown potential antipruritic effects.

Purpose of the Study:

• To investigate the role of spinal CB2R in chronic itch.
• To elucidate the mechanisms by which CB2R activation modulates microglial function and itch signaling.

Main Methods:

• Utilized mouse models of dermatitis and psoriasis.
• Employed conditional Cnr2 deletion in microglia and microglial ablation/inhibition.
• Performed single-cell RNA sequencing and molecular mechanistic studies.
• Investigated neuronal excitability and synaptic transmission in specific neuronal populations.

Main Results:

• Spinal CB2R activation demonstrated significant antipruritic effects.
• Mice lacking Cnr2 exhibited exacerbated itch in dermatitis and psoriasis models.
• CB2R activation reprogrammed microglia, inducing suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related signaling (p38 and STAT1 phosphorylation).
• CB2R activation suppressed neuronal excitability and synaptic transmission via inhibition of microglia-derived cytokines.

Conclusions:

• Microglial activation is a key contributor to chronic itch.
• Spinal CB2R activation in microglia alleviates chronic itch through neuro-immune interactions.
• Targeting microglial CB2R represents a promising therapeutic strategy for chronic itch.