2. Academic Validation
  3. Cannabinoid CB2 receptor controls chronic itch by regulating spinal microglial activation and synaptic transmission

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

  • Cell Rep. 2025 Apr 22;44(4):115559. doi: 10.1016/j.celrep.2025.115559.
Kangtai Xu 1,  Xuefei Liu 2,  Qian Zeng 3,  Yaqi Liu 1,  Leyan Shan 4,  Luyao Ji 4,  Yifei Wu 4,  Jiawei Wu 4,  Yiming Chen 4,  Yitong Li 4,  Songqiang Huang 5,  Changyu Jiang 6,  Xin Hong 7,  Chaoran Wu 8,  Zilong Wang 9
Affiliations

Affiliations

  • 1 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Department of Anesthesiology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 2 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 3 Department of Anesthesiology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, The 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, China.
  • 4 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 5 Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
  • 6 Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, The 6th Affiliated Hospital of Shenzhen University Medical School, Shenzhen, Guangdong, China.
  • 7 Department of Biochemistry, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Key University Laboratory of Metabolism and Health of Guangdong School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China. Electronic address: hongx@sustech.edu.cn.
  • 8 Department of Anesthesiology, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. Electronic address: wu.chaoran@szhospital.com.
  • 9 Department of Medical Neuroscience, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; Key University Laboratory of Metabolism and Health of Guangdong School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China; SUSTech Homeostatic Medicine Institute, SUSTech Center for Pain Medicine, School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China. Electronic address: wangzl6@sustech.edu.cn.
PMID: 40222011 DOI: 10.1016/j.celrep.2025.115559
Abstract

Chronic itch is a devastating clinical condition, and its central mechanisms remain poorly understood. We reported that spinal Cannabinoid Receptor type 2 (CB2R) activation exerts antipruritic effects and that itch escalates in mice lacking Cnr2 in mouse models of dermatitis and psoriasis. In the spinal cord, CB2R is mainly expressed in microglia, and microglial ablation or inhibition attenuated chronic itch, suggesting that microglial activation contributes to chronic itch. Particularly, conditional Cnr2 deletion in microglia also exacerbated chronic itch in mice. Single-cell RNA Sequencing and molecular mechanistic studies suggest that CB2R activation reprogrammed microglia by inducing anti-inflammatory suppressor of cytokine signaling 3 (SOCS3) and reducing itch-related p38 and signal transducer and activator of transcription 1 (STAT1) phosphorylation. Finally, CB2R activation suppressed neuronal excitability and synaptic transmission in gastrin-releasing peptide (GRP)/GRP receptor (GRPR) interneurons and ascending projection neurons by inhibiting microglia-derived cytokines. These findings demonstrate that microglial activation contributes to chronic itch, while CB2R activation in microglia alleviates chronic itch via neuro-immune interactions.

Keywords

CP: Neuroscience; GRPR; SOCS3; STAT1/p38 pathway; cannabinoid receptor type 2; central sensitization; dermatitis; itch; microglia; neuro-immune interactions; spinal cord; synaptic transmission.

Figures
Products
Inhibitors & Agonists
Other Products