PMID- 24984884 OWN - NLM STAT- MEDLINE DCOM- 20150619 LR - 20181202 IS - 1097-4547 (Electronic) IS - 0360-4012 (Linking) VI - 92 IP - 12 DP - 2014 Dec TI - P2X4 receptor in the dorsal horn partially contributes to brain-derived neurotrophic factor oversecretion and toll-like receptor-4 receptor activation associated with bone cancer pain. PG - 1690-702 LID - 10.1002/jnr.23443 [doi] AB - Previous studies have suggested that the microglial P2X7 purinoceptor is involved in the release of tumor necrosis factor-alpha (TNFalpha) following activation of toll-like receptor-4 (TLR4), which is associated with nociceptive behavior. In addition, this progress is evoked by the activation of the P2X4 purinoceptor (P2X4R). Although P2X4R is also localized within spinal microglia in the dorsal horn, little is known about its role in cancer-induced bone pain (CIBP), which is in some ways unique. With the present rat model of CIBP, we demonstrate a critical role of the microglial P2X4R in the enhanced nociceptive transmission, which is associated with TLR4 activation and secretion of brain-derived neurotrophic factor (BDNF) and TNFalpha in the dorsal horn. We assessed mechanical threshold and spontaneous pain of CIBP rats. Moreover, P2X4R small interfering RNA (siRNA) was administered intrathecally, and real-time PCR, Western blots, immunofluorescence histochemistry, and ELISA were used to detect the expression of P2X4R, TLR4, OX-42, phosphorylated-p38 MAPK (p-p38), BDNF, and TNFalpha. Compared with controls, intrathecal injection of P2X4R siRNA could prevent nociceptive behavior induced by ATP plus lipopolysaccharide and CIBP and reduce the expression of P2X4R, TLR4, p-p38, BDNF, and TNFalpha. In addition, the increase of BDNF protein in rat microglial cells depended on P2X4 receptor signaling, which is partially associated with TLR4 activation. The ability of microglial P2X4R to activate TLR4 in spinal cord leading to behavioral hypersensitivity and oversecretion of BDNF could provide an opportunity for the prevention and treatment of CIBP. CI - (c) 2014 Wiley Periodicals, Inc. FAU - Jin, Xiao-Hong AU - Jin XH AD - Department of Anesthesiology, The First Affiliated Hospital of Soochow University, Suzhou City, China. FAU - Wang, Li-Na AU - Wang LN FAU - Zuo, Jian-Ling AU - Zuo JL FAU - Yang, Jian-Ping AU - Yang JP FAU - Liu, Si-Lan AU - Liu SL LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140701 PL - United States TA - J Neurosci Res JT - Journal of neuroscience research JID - 7600111 RN - 0 (Adjuvants, Immunologic) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Lipopolysaccharides) RN - 0 (Receptors, Purinergic P2X4) RN - 0 (Toll-Like Receptor 4) RN - 8L70Q75FXE (Adenosine Triphosphate) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Adenosine Triphosphate/pharmacology MH - Adjuvants, Immunologic/pharmacology MH - Animals MH - Bone Neoplasms/complications MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Carcinoma/complications MH - Cells, Cultured MH - Disease Models, Animal MH - Female MH - Gene Expression Regulation/drug effects MH - Lipopolysaccharides/pharmacology MH - Microglia/metabolism MH - Pain/etiology/*pathology MH - Pain Measurement MH - Posterior Horn Cells/*metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Receptors, Purinergic P2X4/genetics/*metabolism MH - Time Factors MH - Toll-Like Receptor 4/genetics/*metabolism MH - p38 Mitogen-Activated Protein Kinases/metabolism OTO - NOTNLM OT - P2X4 purinoceptor toll-like receptor-4 OT - brain-derived neurotrophic factor OT - cancer induced bone pain OT - microglia OT - rats EDAT- 2014/07/06 06:00 MHDA- 2015/06/20 06:00 CRDT- 2014/07/03 06:00 PHST- 2014/02/05 00:00 [revised] PHST- 2014/04/28 00:00 [revised] PHST- 2014/05/30 00:00 [accepted] PHST- 2014/07/03 06:00 [entrez] PHST- 2014/07/06 06:00 [pubmed] PHST- 2015/06/20 06:00 [medline] AID - 10.1002/jnr.23443 [doi] PST - ppublish SO - J Neurosci Res. 2014 Dec;92(12):1690-702. doi: 10.1002/jnr.23443. Epub 2014 Jul 1.