title: Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of Paclitaxel-induced painful neuropathy.
abstract: Paclitaxel often induces persistent painful neuropathy as its most common treatment-limiting side effect. Little is known concerning the underlying mechanisms. Given the prominent role of glial cells in many types of neuropathic pain, we investigated here the morphological and functional changes of spinal astrocytes and microglia in a rat model of paclitaxel-induced neuropathy. Immunohistochemistry, western blotting, and real-time polymerase chain reaction were performed with samples from 109 rats up to 28 days after paclitaxel treatment. Paclitaxel (2 mg/kg, i.p.) induced a rapid and persistent activation of spinal astrocytes assessed using glial fibrillary acidic protein, but not apparent activation of microglia assessed using OX42, Iba-1, and phosphorylated p38. In the context of astocyte activation, there was a significant downregulation of glial glutamate transporters GLAST and GLT-1 in spinal dorsal horn. The activation of spinal astrocytes by paclitaxel was not associated with expression of pro-inflammatory cytokines including tumor necrosis factor-α, interleukin-1β, or interleukin-6 in spinal dorsal horn. Systemic treatment with minocycline (50 mg/kg, i.p.) prevented activation of astrocytes and downregulation of glial glutamate transporters in spinal dorsal horn induced by paclitaxel. These data suggest the involvement of spinal astrocytes but not microglia in the pathogenesis of paclitaxel-induced neuropathy.
  
  
  CONCLUSIONS
  Spinal astrocytes and/or glial glutamate transporters could be new therapeutic targets for paclitaxel-induced painful neuropathy.
authors.affiliation: Department of Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. haijun.zhang@mdanderson.org
authors.forename: Haijun
authors.initials: H
authors.lastname: Zhang
authors.forename: Seo-Yeon
authors.initials: SY
authors.lastname: Yoon
authors.forename: Hongmei
authors.initials: H
authors.lastname: Zhang
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Dougherty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D017628:Microglia / Q000187:drug effects*; D009437:Neuralgia / Q000139:chemically induced; D017239:Paclitaxel / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D017239:Paclitaxel