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

Acta Pharmacologica Sinica volume 46, pages 1892–1904 (2025)Cite this article

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.

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Fig. 1: Behavioral signature of STA susceptibility.
Fig. 2: DRN GABA-ergic neurons are selectively activated in the susceptible mice.
Fig. 3: Activation of DRN GABA-ergic neurons promotes susceptibility to socially transferred allodynia.
Fig. 4: Inhibition of DRN GABA-ergic neurons promotes resilience to socially transferred allodynia.
Fig. 5: Pharmacological manipulation of MC4R bi-directionally regulates DRN GABA-ergic neuron activity.
Fig. 6: α-MSH in the DRN promotes resilience to socially transferred allodynia.
Fig. 7: HS014 in the DRN promotes susceptibility to socially transferred allodynia.
Fig. 8: Inter-individual differences in social transfer of pain: the functional role of DRN GABA-ergic neuron and its underlying molecular mechanism.

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Data will be made available on request.

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Acknowledgements

The present study was supported by the STI2030-Major Projects (2021ZD0203100), National Natural Science Foundation of China (31970937, 82271255 and 82301413), Jiangsu Province Innovative and Entrepreneurial Team Program, Jiangsu Province Key R&D Program Social Development Project (BE2023690), China Postdoctoral Science Foundation (2023M732973), Science and Technology Department of Jiangsu Province (BK20210908, BK20241956), Xuzhou Medical University start-up grant for excellent scientist (D2020053, RC20552033, D2022005) and the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX22_2932, KYCX22_2918, KYCX23_2998 and KYCX23_2952). We thank Liwen Bianji (Edanz) (www.liwenbianji.cn) for editing the English text of a draft of this manuscript.

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  1. These authors contributed equally: Lin Ai, Yi Han, Ting Ge, Sha Sha

Authors and Affiliations

  1. Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, 221004, China

    Lin Ai, Yi Han, Ting Ge, Sha Sha, Xiao-jing Zhai, Ran Ji, Yu Zhou, Dan-dan Chen, An Xie, Wen-xin Zhang, Zhou Wu, Mo-ruo Zhang, Jun-xia Yang, Jun-li Cao, Ling-zhen Song & Hong-xing Zhang

  2. Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, Xuzhou Medical University, Xuzhou, 221004, China

    Lin Ai, Yi Han, Ting Ge, Sha Sha, Xiao-jing Zhai, Ran Ji, Yu Zhou, Dan-dan Chen, An Xie, Wen-xin Zhang, Zhou Wu, Mo-ruo Zhang, Jun-xia Yang, Jun-li Cao, Ling-zhen Song & Hong-xing Zhang

  3. NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Xuzhou, 221004, China

    Lin Ai, Yi Han, Ting Ge, Sha Sha, Xiao-jing Zhai, Ran Ji, Yu Zhou, Dan-dan Chen, An Xie, Wen-xin Zhang, Zhou Wu, Mo-ruo Zhang, Jun-xia Yang, Jun-li Cao, Ling-zhen Song & Hong-xing Zhang

  4. Laboratory Animal Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, 221004, China

    An-kang Hu

  5. Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China

    Jun-li Cao

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  1. Lin Ai
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Contributions

Conceptualization: HXZ, LA; Methodology: LA, YH; Investigation: LA, YH, TG, SS, XJZ, RJ, YZ, DDC, AX, WXZ, ZW, MRZ, JXY; Funding acquisition: HXZ, LZS, JLC, LA, YH, XJZ; Project administration: HXZ, LA; Supervision: HXZ, LZS, AKH; Writing – original draft: HXZ, LA; Writing – review & editing: HXZ, LA; LA, YH, TG, and SS contributed equally to this work.

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Correspondence to Jun-li Cao, Ling-zhen Song or Hong-xing Zhang.

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Ai, L., Han, Y., Ge, T. et al. Dorsal raphe GABA-ergic neurons regulate the susceptibility to social transfer of pain in mice. Acta Pharmacol Sin 46, 1892–1904 (2025). https://doi.org/10.1038/s41401-025-01494-x

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