title: Brain-derived neurotrophic factor modulates N-methyl-D-aspartate receptor activation in a rat model of cancer-induced bone pain.
abstract: Brain-derived neurotrophic factor (BDNF) released within the spinal cord induces phosphorylation of N-methyl-D-aspartate (NMDA) receptors on the spinal cord neurons. This process is necessary for maintaining pain hypersensitivity after nerve injury. However, little is known about the role of BDNF and NMDA receptors in cancer-induced bone pain (CIBP), whose features are unique. This study demonstrates a critical role of the BDNF-modulated NMDA subunit 1 (NR1) in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP, both in the spinal cord and in the dorsal root ganglia (DRG). We selectively suppressed BDNF expression by RNA interference (RNAi) using intrathecal administration of BDNF small interfering RNA (siRNA). Then, we assessed mechanical threshold and spontaneous pain in CIBP rats. Real-time PCR, Western blotting, and fluorescent immunohistochemical staining were used to detect BDNF or NR1 both in vivo and in vitro. BDNF and phospho-NR1 were expressed under CIBP experimental conditions, with expression levels peaking at day 6 (BDNF) or 9 (NR1). Intrathecal BDNF siRNA prevented CIBP at an early stage of tumor growth (days 4-6). However, at later stages (days 10-12), intrathecal BDNF siRNA only attenuated, but did not completely block, the established CIBP. BDNF-induced NMDA receptor activation in the spinal cord or DRG leads to central sensitization and behavioral hypersensitivity. Thus, BDNF might provide a targeting opportunity for alleviating CIBP.
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou City, Jiangsu Province, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Wang
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Yang
authors.forename: Fu-Hai
authors.initials: FH
authors.lastname: Ji
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhan
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Jin
authors.forename: Qi-Nian
authors.initials: QN
authors.lastname: Xu
authors.forename: Xiu-Yun
authors.initials: XY
authors.lastname: Wang
authors.forename: Jian-Ling
authors.initials: JL
authors.lastname: Zuo
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy / Q000209:etiology; D000704:Analysis of Variance; D000818:Animals; D001859:Bone Neoplasms / Q000150:complications*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000473:pathology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C409466:NR1 NMDA receptor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016194:Receptors, N-Methyl-D-Aspartate