Enhancing neuronal chloride extrusion rescues α2/α3 GABAA-mediated analgesia in neuropathic pain

被引:0
|
作者
Louis-Etienne Lorenzo
Antoine G. Godin
Francesco Ferrini
Karine Bachand
Isabel Plasencia-Fernandez
Simon Labrecque
Alexandre A. Girard
Dominic Boudreau
Irenej Kianicka
Martin Gagnon
Nicolas Doyon
Alfredo Ribeiro-da-Silva
Yves De Koninck
机构
[1] Quebec Mental Health Institute,CERVO Brain Research Centre
[2] McGill University,Department of Pharmacology & Therapeutics
[3] Université Laval,Department of Psychiatry & Neuroscience
[4] Université Laval,Graduate program in Neuroscience
[5] University of Turin,Department of Veterinary Sciences
[6] IP Paris,Ecole Polytechnique
[7] Chlorion Pharma,Centre for Innovation
[8] Laval,Finite Element Interdisciplinary Research Group (GIREF)
[9] University of Otago,Department of Anatomy & Cell Biology
[10] Université Laval,Alan Edwards Centre for Research on Pain
[11] McGill University,undefined
[12] McGill University,undefined
[13] Laurent Pharmaceuticals Inc.,undefined
来源
Nature Communications | / 11卷
关键词
D O I
暂无
中图分类号
学科分类号
摘要
Spinal disinhibition has been hypothesized to underlie pain hypersensitivity in neuropathic pain. Apparently contradictory mechanisms have been reported, raising questions on the best target to produce analgesia. Here, we show that nerve injury is associated with a reduction in the number of inhibitory synapses in the spinal dorsal horn. Paradoxically, this is accompanied by a BDNF-TrkB-mediated upregulation of synaptic GABAARs and by an α1-to-α2GABAAR subunit switch, providing a mechanistic rationale for the analgesic action of the α2,3GABAAR benzodiazepine-site ligand L838,417 after nerve injury. Yet, we demonstrate that impaired Cl- extrusion underlies the failure of L838,417 to induce analgesia at high doses due to a resulting collapse in Cl- gradient, dramatically limiting the benzodiazepine therapeutic window. In turn, enhancing KCC2 activity not only potentiated L838,417-induced analgesia, it rescued its analgesic potential at high doses, revealing a novel strategy for analgesia in pathological pain, by combined targeting of the appropriate GABAAR-subtypes and restoring Cl- homeostasis.
引用
收藏
相关论文
共 50 条
  • [31] N-Methyl-D-aspartate Receptor- and Calpain-mediated Proteolytic Cleavage of K+-Cl- Cotransporter-2 Impairs Spinal Chloride Homeostasis in Neuropathic Pain
    Zhou, Hong-Yi
    Chen, Shao-Rui
    Byun, Hee-Sun
    Chen, Hong
    Li, Li
    Han, Hee-Dong
    Lopez-Berestein, Gabriel
    Sood, Anil K.
    Pan, Hui-Lin
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (40) : 33853 - 33864
  • [32] The effect of sinomenine in diabetic neuropathic pain mediated by the P2X3 receptor in dorsal root ganglia (vol 13, pg 227, 2017)
    Rao, Shenqiang
    Liu, Shuangmei
    Zou, Lifang
    Jia, Tianyu
    Zhao, Shanhong
    Wu, Bing
    Yi, Zhihua
    Wang, Shouyu
    Xue, Yun
    Gao, Yun
    Xu, Changshui
    Li, Guilin
    Xu, Hong
    Zhang, Chunping
    Liang, Shangdong
    PURINERGIC SIGNALLING, 2017, 13 (02) : 237 - 237
  • [33] Correction to: lncRNA NONRATT021972 siRNA Decreases Diabetic Neuropathic Pain Mediated by the P2X3 Receptor in Dorsal Root Ganglia
    Haiying Peng
    Lifang Zou
    Jinyan Xie
    Hong Wu
    Bing Wu
    Gaochun Zhu
    Qiulan Lv
    Xi Zhang
    Shuangmei Liu
    Guilin Li
    Hong Xu
    Yun Gao
    Changshui Xu
    Chunping Zhang
    Shouyu Wang
    Yun Xue
    Shangdong Liang
    Molecular Neurobiology, 2019, 56 : 6656 - 6657
  • [34] Increased hyperalgesia by 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a chloride channel blocker in crush injury-induced neuropathic pain in rats
    Ramteke, Vinod D.
    Tandan, Surendra K.
    Kumar, Dinesh
    Devi, R. Arun
    Shukla, Manoj K.
    Prakash, Vellanki Ravi
    PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 2009, 91 (03) : 417 - 422
  • [35] PolyphyllinVI alleviates the spared nerve injury-induced neuropathic pain based on P2X3 receptor-mediated the release of inflammatory mediators
    Yi, Mengqin
    Zhang, Zhenglang
    Luo, Zhenhui
    Luo, Anqi
    Zeng, Hekun
    Li, Peiyang
    Wang, Tingting
    Yang, Jingwen
    Nie, Hong
    JOURNAL OF ETHNOPHARMACOLOGY, 2024, 325
  • [36] Probucol attenuates NF-ΚB/NLRP3 signalling and augments Nrf-2 mediated antioxidant defence in nerve injury induced neuropathic pain
    Derangula, Kalyani
    Javalgekar, Mohit
    Arruri, Vijay Kumar
    Gundu, Chayanika
    Kalvala, Anil Kumar
    Kumar, Ashutosh
    INTERNATIONAL IMMUNOPHARMACOLOGY, 2022, 102
  • [37] VEGF and its receptor-2 involved in neuropathic pain transmission mediated by P2X2/3 receptor of primary sensory neurons (vol 83, pg 284, 2010)
    Lin, Jiari
    Li, Guilin
    Den, Xiaorong
    Xu, Changshui
    Liu, Shuangmei
    Gao, Yun
    Liu, Han
    Zhang, Jun
    Li, Xin
    Liang, Shangdong
    BRAIN RESEARCH BULLETIN, 2020, 163 : 194 - 196
  • [38] POU2F1/DNMT3a Pathway Participates in Neuropathic Pain by Hypermethylation-Mediated LRFN4 Downregulation Following Oxaliplatin Treatment
    Gu, Yan-Hui
    Wang, Jing
    Lu, Wei-Cheng
    Cheng, Yong
    Tao, Rong
    Zhang, Shi-Jia
    Xu, Ting
    Zhai, Ke-Wei
    Luo, Su-Xia
    Xin, Wen-Jun
    NEUROCHEMICAL RESEARCH, 2023, 48 (12) : 3652 - 3664
  • [39] POU2F1/DNMT3a Pathway Participates in Neuropathic Pain by Hypermethylation-Mediated LRFN4 Downregulation Following Oxaliplatin Treatment
    Yan-Hui Gu
    Jing Wang
    Wei-Cheng Lu
    Yong Cheng
    Rong Tao
    Shi-Jia Zhang
    Ting Xu
    Ke-Wei Zhai
    Su-Xia Luo
    Wen-Jun Xin
    Neurochemical Research, 2023, 48 : 3652 - 3664
  • [40] Sirtuin 3 Mediated by Spinal cMyc-Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model
    Zhu, Xun
    Yi, Hyun
    Gu, Jun
    Liu, Shue
    Hayashi, Kentaro
    Ikegami, Daigo
    Pardo, Marta
    Toborek, Michal
    Roy, Sabita
    Li, Heng
    Levitt, Roy C.
    Hao, Shuanglin
    ANESTHESIA AND ANALGESIA, 2024, 139 (03): : 647 - 659