title: Involvement of the chemokine CCL3 and the purinoceptor P2X7 in the spinal cord in paclitaxel-induced mechanical allodynia.
abstract: BACKGROUND
  Paclitaxel is an effective chemotherapeutic agent widely used for the treatment of solid tumors. The major dose-limiting toxicity of paclitaxel is peripheral neuropathy. The mechanisms underlying the development and maintenance of paclitaxel-induced peripheral neuropathy are still unclear, and there are no currently established effective treatments. Accumulating evidence in models of neuropathic pain in which peripheral nerves are lesioned has implicated spinal microglia and chemokines in pain hypersensitivity, but little is know about their roles in chemotherapy-induced peripheral neuropathy. In the present study, we investigated the role of CC-chemokine ligand 3 (CCL3) in the spinal cord in the development and maintenance of mechanical allodynia using a rat model of paclitaxel-induced neuropathy.
  
  
  RESULTS
  Repeated intravenous administration of paclitaxel induced a marked decrease in paw withdrawal threshold in response to mechanical stimulation (mechanical allodynia). In these rats, the number of microglia in the spinal dorsal horn (SDH) was significantly increased. Paclitaxel-treated rats showed a significant increase in the expression of mRNAs for CCL3 and its receptor CCR5 in the SDH. Intrathecal administration of a CCL3-neutralizing antibody not only attenuated the development of paclitaxel-induced mechanical allodynia but also reversed its maintenance. Paclitaxel also upregulated expression of purinoceptor P2X7 receptors (P2X7Rs), which have been implicated in the release of CCL3 from microglia, in the SDH. The selective P2X7R antagonist A438079 had preventive and reversal effects on paclitaxel-induced allodynia.
  
  
  CONCLUSIONS
  Our findings suggest a contribution of CCL3 and P2X7Rs in the SDH to paclitaxel-induced allodynia and may provide new therapeutic targets for paclitaxel-induced painful neuropathy.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Ochi-ishi
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nagata
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Inoue
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Tozaki-Saitoh
authors.forename: Makoto
authors.initials: M
authors.lastname: Tsuda
authors.affiliation: Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 MaidashiHigashi-ku, Fukuoka 812-8582, Japan. inoue@phar.kyushu-u.ac.jp.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Inoue
mesh_terms: D000818:Animals; D000906:Antibodies / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity*; D054405:Chemokine CCL3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D017239:Paclitaxel / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000906:Antibodies; D000972:Antineoplastic Agents, Phytogenic; D054405:Chemokine CCL3; D012333:RNA, Messenger; D019713:Receptors, CCR5; D058486:Receptors, Purinergic P2X7; D017239:Paclitaxel