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

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-Ren Tao, Thomas Kuner, Xu Zhang, Rohini Kuner, Sheng-Xi Wu () and Ceng Luo ()
Additional contact information
Rou-Gang Xie: Fourth Military Medical University
Wen-Guang Chu: Fourth Military Medical University
Da-Lu Liu: Fourth Military Medical University
Xu Wang: Fourth Military Medical 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

Nature Communications, 2022, vol. 13, issue 1, 1-23

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28429-y

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