title: Robust spinal neuroinflammation mediates mechanical allodynia in Walker 256 induced bone cancer rats.
abstract: It has been reported that remarkable and sustained activation of astrocytes and/or microglia occurs in cancer induced pain (CIP), which is different from neuropathic and inflammatory pain. The present study was designed to investigate the role of spinal Toll-like receptor 4 (TLR4) induced glial neuroinflammation in cancer induced pain using a modified rat model of bone cancer. The rat model of CIP consisted of unilateral intra-tibial injection with Walker 256 mammary gland carcinoma. Nine days after Walker 256 inoculation, a robust activation of both astrocytes and microglia in bilateral spinal dorsal horn was observed together with significant bilateral mechanical allodynia. This neuroinflammation was characterized by enhanced immunostaining of both glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker), and an elevated level of IL-1β, IL-6 and TNF-α mRNA. I.t. administration of fluorocitrate (an inhibitor of glial metabolism, 1 nmol) or minocycline (an inhibitor of microglia, 100 μg) has significant anti-allodynic effects on day 12 after Walker 256 inoculation. Naloxone (a nonstereoselective TLR4 signaling blocker, 60 μg, i.t.) also significantly alleviated mechanical allodynia and simultaneously blocked the increased inflammatory cytokine mRNA. The results suggested that spinal TLR4 might play an important role in the sustained glial activation that critically contributed to the robust and sustained spinal neuroinflammation in CIP. This result could potentially help clinicians and researchers to better understand the mechanism of complicated cancer pain.
authors.affiliation: Department of Integrative Medicine and Neurobiology, Shanghai Medical College, Institute of Acupuncture Research, Institutes of Brain Science, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China.
authors.forename: Qi-Liang
authors.initials: QL
authors.lastname: Mao-Ying
authors.forename: Xiao-Wei
authors.initials: XW
authors.lastname: Wang
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Yang
authors.forename: Xiu
authors.initials: X
authors.lastname: Li
authors.forename: Wen-Li
authors.initials: WL
authors.lastname: Mi
authors.forename: Gen-Cheng
authors.initials: GC
authors.lastname: Wu
authors.forename: Yan-Qing
authors.initials: YQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D039481:CD11b Antigen / Q000378:metabolism; D002279:Carcinoma 256, Walker / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000150:complications* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D006984:Hypertrophy; D007249:Inflammation / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009368:Neoplasm Transplantation; D010146:Pain / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D017288:Pain Threshold; D020671:Posterior Horn Cells / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013977:Tibia / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D016207:Cytokines; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4