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Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain

Author

Listed:
  • Rou-Gang Xie

    (Fourth Military Medical University)

  • Wen-Guang Chu

    (Fourth Military Medical University)

  • Da-Lu Liu

    (Fourth Military Medical University
    Fourth Military Medical University)

  • Xu Wang

    (Fourth Military Medical University
    Yanan University)

  • Sui-Bin Ma

    (Fourth Military Medical University)

  • Fei Wang

    (Fourth Military Medical University)

  • Fu-Dong Wang

    (Fourth Military Medical University)

  • Zhen Lin

    (Fourth Military Medical University)

  • Wen-Bin Wu

    (Fourth Military Medical University)

  • Na Lu

    (Fourth Military Medical University)

  • Ying-Ying Liu

    (Fourth Military Medical University)

  • Wen-Juan Han

    (Fourth Military Medical University)

  • Hui Zhang

    (Fourth Military Medical University)

  • Zhan-Tao Bai

    (Yanan University)

  • San-Jue Hu

    (Fourth Military Medical University)

  • Hui-Ren Tao

    (Shenzhen University General Hospital)

  • Thomas Kuner

    (University of Heidelberg, Im Neuenheimer Feld 307)

  • Xu Zhang

    (Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences)

  • Rohini Kuner

    (University of Heidelberg, Im Neuenheimer Feld 366)

  • Sheng-Xi Wu

    (Fourth Military Medical University)

  • Ceng Luo

    (Fourth Military Medical University)

Abstract

Postsynaptic NMDARs at spinal synapses are required for postsynaptic long-term potentiation and chronic pain. However, how presynaptic NMDARs (PreNMDARs) in spinal nociceptor terminals control presynaptic plasticity and pain hypersensitivity has remained unclear. Here we report that PreNMDARs in spinal nociceptor terminals modulate synaptic transmission in a nociceptive tone-dependent manner. PreNMDARs depresses presynaptic transmission in basal state, while paradoxically causing presynaptic potentiation upon injury. This state-dependent modulation is dependent on Ca2+ influx via PreNMDARs. Small conductance Ca2+-activated K+ (SK) channels are responsible for PreNMDARs-mediated synaptic depression. Rather, tissue inflammation induces PreNMDARs-PKG-I-dependent BDNF secretion from spinal nociceptor terminals, leading to SK channels downregulation, which in turn converts presynaptic depression to potentiation. Our findings shed light on the state-dependent characteristics of PreNMDARs in spinal nociceptor terminals on modulating nociceptive transmission and revealed a mechanism underlying state-dependent transition. Moreover, we identify PreNMDARs in spinal nociceptor terminals as key constituents of activity-dependent pain sensitization.

Suggested Citation

  • Rou-Gang Xie & Wen-Guang Chu & Da-Lu Liu & Xu Wang & Sui-Bin Ma & Fei Wang & Fu-Dong Wang & Zhen Lin & Wen-Bin Wu & Na Lu & Ying-Ying Liu & Wen-Juan Han & Hui Zhang & Zhan-Tao Bai & San-Jue Hu & Hui-R, 2022. "Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain," Nature Communications, Nature, vol. 13(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28429-y
    DOI: 10.1038/s41467-022-28429-y
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    References listed on IDEAS

    as
    1. Hantao Liu & Patrick W. Mantyh & Allan I. Basbaum, 1997. "NMDA-receptor regulation of substance P release from primary afferent nociceptors," Nature, Nature, vol. 386(6626), pages 721-724, April.
    2. Paul T E Cusack, 2020. "On Pain," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 31(3), pages 24253-24254, October.
    3. Yann Humeau & Hamdy Shaban & Stephanie Bissière & Andreas Lüthi, 2003. "Presynaptic induction of heterosynaptic associative plasticity in the mammalian brain," Nature, Nature, vol. 426(6968), pages 841-845, December.
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