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  3. Dorsal raphe GABA-ergic neurons regulate the susceptibility to social transfer of pain in mice

Dorsal raphe GABA-ergic neurons regulate the susceptibility to social transfer of pain in mice

  • Acta Pharmacol Sin. 2025 Feb 26. doi: 10.1038/s41401-025-01494-x.
Lin Ai # 1 2 3,  Yi Han # 1 2 3,  Ting Ge # 1 2 3,  Sha Sha # 1 2 3,  Xiao-Jing Zhai 1 2 3,  Ran Ji 1 2 3,  Yu Zhou 1 2 3,  Dan-Dan Chen 1 2 3,  An Xie 1 2 3,  Wen-Xin Zhang 1 2 3,  Zhou Wu 1 2 3,  Mo-Ruo Zhang 1 2 3,  Jun-Xia Yang 1 2 3,  An-Kang Hu 4,  Jun-Li Cao 5 6 7 8,  Ling-Zhen Song 9 10 11,  Hong-Xing Zhang 12 13 14
Affiliations

Affiliations

  • 1 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 2 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 3 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China.
  • 4 Laboratory Animal Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221004, China.
  • 5 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. caojl0310@aliyun.com.
  • 6 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China. caojl0310@aliyun.com.
  • 7 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China. caojl0310@aliyun.com.
  • 8 Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China. caojl0310@aliyun.com.
  • 9 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. lingzhen.song@xzhmu.edu.cn.
  • 10 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China. lingzhen.song@xzhmu.edu.cn.
  • 11 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China. lingzhen.song@xzhmu.edu.cn.
  • 12 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China. hongxing.zhang@xzhmu.edu.cn.
  • 13 Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China. hongxing.zhang@xzhmu.edu.cn.
  • 14 NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China. hongxing.zhang@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 40011629 DOI: 10.1038/s41401-025-01494-x
Abstract

Some individuals are more susceptible to developing or suffering from pain states than Others. However, the brain mechanisms underlying the susceptibility to pain responses are unknown. In this study, we defined pain susceptibility by recapitulating inter-individual differences in pain responses in mice exposed to a paradigm of socially transferred allodynia (STA), and with a combination of chemogenetic, molecular, pharmacological and electrophysiological approaches, we identified GABA-ergic neurons in the dorsal raphe nucleus (DRN) as a cellular target for the development and maintenance of STA susceptibility. We showed that DRN GABA-ergic neurons were selectively activated in STA-susceptible mice when compared with the unsusceptible (resilient) or control mice. Chemogenetic activation of DRN GABA-ergic neurons promoted STA susceptibility; whereas inhibiting these neurons prevented the development of STA susceptibility and reversed established STA. In in vitro slice electrophysiological analysis, we demonstrated that melanocortin 4 receptor (MC4R) enriched in DRN GABA-ergic neurons was a molecular target for regulating pain susceptibility, possibly by affecting DRN GABA-ergic neuronal activity. These results establish the DRN GABA-ergic neurons as an essential target for controlling pain susceptibility, thus providing important information for developing conceptually innovative and more accurate analgesic strategies.

Keywords

GABA; chemogenetics; dorsal raphe nucleus; melanocortin 4 receptor; pain susceptibility; social transfer of allodynia.

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