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Identification of spinal circuits involved in touch-evoked dynamic mechanical pain

Nature Neuroscience volume 20, pages 804814 (2017) | Download Citation

Abstract

Mechanical hypersensitivity is a debilitating symptom for millions of chronic pain patients. It exists in distinct forms, including brush-evoked dynamic and filament-evoked punctate hypersensitivities. We reduced dynamic mechanical hypersensitivity induced by nerve injury or inflammation in mice by ablating a group of adult spinal neurons defined by developmental co-expression of VGLUT3 and Lbx1 (VT3Lbx1 neurons): the mice lost brush-evoked nocifensive responses and conditional place aversion. Electrophysiological recordings show that VT3Lbx1 neurons form morphine-resistant polysynaptic pathways relaying inputs from low-threshold Aβ mechanoreceptors to lamina I output neurons. The subset of somatostatin-lineage neurons preserved in VT3Lbx1-neuron-ablated mice is largely sufficient to mediate morphine-sensitive and morphine-resistant forms of von Frey filament-evoked punctate mechanical hypersensitivity. Furthermore, acute silencing of VT3Lbx1 neurons attenuated pre-established dynamic mechanical hypersensitivity induced by nerve injury, suggesting that these neurons may be a cellular target for treating this form of neuropathic pain.

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Acknowledgements

We thank E.J. Cobos, who developed the protocol for measuring brush-evoked dynamic mechanical hypersensitivity. We thank S. Dymecki for the ROSA26-LSL-FSF-hM4Di and ROSA26-Flpe mice, Z.J. Huang and the Jackson laboratory for the SOM-IRES-Cre (SOMCre) mice, and the Allen Brain Institute and the Jackson Laboratory for the ROSA26-lsl-tdTomato mice. We thank W. Knowlton for her assistance with thermal pain measurement and D. Zhou (Shanghai Medviser Co. Ltd.) for his assistance with figure preparation. The work was supported by NIH grants to Q.M. and M.G. (R01 NS086372), to Q.M. (R01 DE018025 and R01 NS072031) and to B.B.L. (R01 DK111401, R01 DK075632, R01 DK096010, R01 DK089044, P30 DK046200-BNORC Transgenic core and P30 DK057521-BADERC Transgenic core). Y.W., L.C. and Y.Z. were supported by Grants from National Natural Science Fund of China (31471027, 31571085 and 81100815, 31300922) and by the 111 Project of China.

Author information

Author notes

    • Bo Duan

    Present address: Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA.

    • Longzhen Cheng
    • , Bo Duan
    •  & Tianwen Huang

    These authors contributed equally to this work.

Affiliations

  1. Institute of Brain Science, the State Key Laboratory of Medical Neurobiology and the Collaborative Innovation Center for Brain Science, Fudan University, Shanghai, China.

    • Longzhen Cheng
    • , Yangyang Chen
    •  & Yun Wang
  2. Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.

    • Longzhen Cheng
    • , Bo Duan
    • , Tianwen Huang
    • , Yan Zhang
    • , Xiangyu Ren
    •  & Qiufu Ma
  3. Cell Electrophysiology Laboratory, Wannan Medical College, Wuhu, China.

    • Yan Zhang
  4. Molecular Neurobiology Laboratory, the Salk Institute for Biological Studies, La Jolla, California, USA.

    • Olivier Britz
    • , Lidia Garcia-Campmany
    • , Xiangyu Ren
    •  & Martyn Goulding
  5. Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.

    • Linh Vong
    •  & Bradford B Lowell

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Contributions

L.C., B.D., T.H., Q.M. and Y.W. designed the study. L.C. and Y.Z. performed electrophysiological experiments and analyzed the recording data. B.D., T.H., X.R. and Y.C. performed histochemical and behavioral experiments and analyzed the data. O.B., L.G.-C. and M.G. provided intersectional ablation mouse lines before publication. L.V. and B.B.L. generated the VT3Cre mice. Q.M. and Y.W. supervised the whole study. Q.M., L.C., B.D., T.H., M.G. and Y.W. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Yun Wang or Qiufu Ma.

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DOI

https://doi.org/10.1038/nn.4549

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