title: The astrocyte-targeted therapy by Bushi for the neuropathic pain in mice.
abstract: BACKGROUND
  There is accumulating evidence that the activation of spinal glial cells, especially microglia, is a key event in the pathogenesis of neuropathic pain. However, the inhibition of microglial activation is often ineffective, especially for long-lasting persistent neuropathic pain. So far, neuropathic pain remains largely intractable and a new therapeutic strategy for the pain is still required.
  
  
  RESULTS
  Using Seltzer model mice, we investigated the temporal aspect of two types of neuropathic pain behaviors, i.e., thermal hyperalgesia and mechanical allodynia, as well as that of morphological changes in spinal microglia and astrocytes by immunohistochemical studies. Firstly, we analyzed the pattern of progression in the pain behaviors, and found that the pain consisted of an "early induction phase" and subsequent "late maintenance phase". We next analyzed the temporal changes in spinal glial cells, and found that the induction and the maintenance phase of pain were associated with the activation of microglia and astrocytes, respectively. When Bushi, a Japanese herbal medicine often used for several types of persistent pain, was administered chronically, it inhibited the maintenance phase of pain without affecting the induction phase, which was in accordance with the inhibition of astrocytic activation in the spinal cord. These analgesic effects and the inhibition of astrocytic activation by Bushi were mimicked by the intrathecal injection of fluorocitrate, an inhibitor of astrocytic activation. Finally, we tested the direct effect of Bushi on astrocytic activation, and found that Bushi suppressed the IL-1β- or IL-18-evoked ERK1/2-phosphorylation in cultured astrocytes but not the ATP-evoked p38- and ERK1/2-phosphorylation in microglia in vitro.
  
  
  CONCLUSIONS
  Our results indicated that the activation of spinal astrocytes was responsible for the late maintenance phase of neuropathic pain in the Seltzer model mice and, therefore, the inhibition of astrocytic activation by Bushi could be a useful therapeutic strategy for treating neuropathic pain.
authors.affiliation: Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shibata
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugawara
authors.forename: Kayoko
authors.initials: K
authors.lastname: Fujishita
authors.forename: Youichi
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsukawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Schuichi
authors.initials: S
authors.lastname: Koizumi
mesh_terms: D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D002951:Citrates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D051379:Mice; D008813:Mice, Inbred ICR; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008911:Minocycline / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D010147:Pain Measurement; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology* / Q000627:therapeutic use*; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D013997:Time Factors
chemical_list: D000700:Analgesics; D002951:Citrates; D010936:Plant Extracts; C568891:bushi; C007744:fluorocitrate; D008911:Minocycline