title: Anti-nociceptive roles of the glia-specific metabolic inhibitor fluorocitrate in paclitaxel-evoked neuropathic pain.
abstract: Paclitaxel (Taxol) is a powerful chemotherapy drug used in breast cancers, but it often causes neuropathic pain, leading to the early cessation of therapy and poor treatment outcomes. Approaches for the management of paclitaxel-induced neuropathic pain are urgently needed. The involvement of spinal astrocytes in the pathogenesis of paclitaxel-induced neuropathy has been reported, but little is known about the role of fluorocitrate (FC), a selective inhibitor of astrocyte activation, during neuropathic pain related to paclitaxel treatment. In this study, we investigated the effects of FC on paclitaxel-induced neuropathic pain. Glial fibrillary acidic protein (GFAP) expression was determined to assess astrocyte activation. To explore the mechanisms involved, the expression of glial glutamate transporter 1 (GLT-1) and the activation of mitogen-activated protein kinases in the spinal dorsal horn were analyzed. The results showed that paclitaxel decreased the mechanical nociceptive thresholds and increased GFAP expression, leading to spinal astrocyte activation. After paclitaxel treatment, GLT-1 was significantly down-regulated, and the phosphorylation of ERK1/2 and JNK were obviously up-regulated. However, paclitaxel treatment did not increase p38 phosphorylation. Additional studies showed that paclitaxel-evoked mechanical hypersensitivity was reduced by FC treatment. Moreover, FC treatment inhibited the activation of astrocytes and reversed the changes in GLT-1 expression and MAPK phosphorylation. Further study indicated that FC did not influence the antitumor effect of paclitaxel, suggesting that FC blocked paclitaxel-induced neuropathic pain without antagonizing its antitumor effect. Together, these results suggested that paclitaxel induced astrocyte-specific activation, which may contribute to mechanical allodynia and hyperalgesia, and that FC could be a potential therapeutic agent for paclitaxel-induced neuropathic pain.
authors: Pain Management Center and Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
authors: Yongming
authors: Y
authors: Xu
authors: Department of Clinical Laboratory, Jinan Infectious Disease Hospital, Shandong University, Jinan 250021, China.
authors: Guangxia
authors: G
authors: Cheng
authors: Department of Clinical Laboratory, Liaocheng People's Hospital, Liaocheng 252000, China.
authors: Yanrong
authors: Y
authors: Zhu
authors: Pain Management Center and Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
authors: Xin
authors: X
authors: Zhang
authors: Pain Management Center and Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
authors: Shaofeng
authors: S
authors: Pu
authors: Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
authors: Junzhen
authors: J
authors: Wu
authors: Pain Management Center and Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China.
authors: Yingying
authors: Y
authors: Lv
authors: Pain Management Center and Department of Anesthesiology, Shanghai Sixth People's Hospital, Shanghai Jiaotong University, Shanghai 200233, China dudongping@hotmail.com.
authors: Dongping
authors: D
authors: Du
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000633:toxicity; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002951:Citrates / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D008297:Male; D008856:Microscopy, Fluorescence; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology* / Q000633:toxicity; D010147:Pain Measurement / Q000379:methods; D017207:Rats, Sprague-Dawley; D066148:Spinal Cord Dorsal Horn / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology
chemical_list: D000700:Analgesics; D000972:Antineoplastic Agents, Phytogenic; D002951:Citrates; D027342:Excitatory Amino Acid Transporter 2; D005904:Glial Fibrillary Acidic Protein; C493395:Slc1a2 protein, rat; C007744:fluorocitrate; D020928:Mitogen-Activated Protein Kinases; D017239:Paclitaxel
keywords: astrocyte; fluorocitrate; neuropathic pain; paclitaxel