title: BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation.
abstract: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury.
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: dingxu@bjmu.edu.cn.
authors.forename: Xu
authors.initials: X
authors.lastname: Ding
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: 15810017232@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Cai
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: lisong0115@163.com.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: liuxiaodan@bjmu.edu.cn.
authors.forename: Xiao-Dan
authors.initials: XD
authors.lastname: Liu
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China. Electronic address: ywan@hsc.pku.edu.cn.
authors.forename: You
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Neuroscience Research Institute, Peking University, Beijing 100191, P.R. China; Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, P.R. China; Key Laboratory for Neuroscience, Ministry of Education and Ministry of Health, Beijing 100191, P.R. China. Electronic address: ggxing@bjmu.edu.cn.
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Xing
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000188:drug therapy / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D066148:Spinal Cord Dorsal Horn / Q000378:metabolism*; D013127:Spinal Nerves / Q000293:injuries
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C121001:NR2B NMDA receptor; C512715:NSC-87877; D011804:Quinolines; D016194:Receptors, N-Methyl-D-Aspartate; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11
keywords: Brain-derived neurotrophic factor; GluN2B-containing NMDA receptor; Long-term potentiation; Neuropathic pain; SHP2; Spinal dorsal horn