title: Intrathecal CGS-26303 Pretreatment Attenuates Spinal Nerve Ligation-Induced Neuropathic Pain in the Spinal Cord.
abstract: BACKGROUND
  Matrix metalloproteinase (MMPs) and endothelin-1 may prove to be important in the generation of pain induced by inflammation and nerve lesion. This study aimed to investigate the relationship between endothelin receptors and MMPs.
  
  
  METHODS
  Male Sprague-Dawley rats (250-300 g) were divided into 5 groups: a normal (control) group; an L5 spinal nerve ligation (SNL) group; a CGS-26303 IT + L5 SNL group; a BQ-123 IT + L5 SNL group; and a BQ-788 IT + L5 SNL group. The expression of glial fibrillary acidic protein, endothelin-A receptor (ETAR), endothelin-B receptor, MMP-2, and MMP-9 in the ipsilateral L5 dorsal root ganglion (DRG) and the activation of microglia and astrocytes in the L5 spinal dorsal horn (SDH) were quantified by immunofluorescence and Western blotting.
  
  
  RESULTS
  Intrathecal pretreatment with CGS-26303 significantly attenuated the hyperalgesic and mechanical responses induced by SNL for 4 days, whereas BQ-123 administration alleviated the hyperalgesia only for 3 hours and mechanical allodynia for only 1 hour. Pretreatment with CGS-26303 significantly down-regulated the glial fibrillary acidic protein, ET-A, MMP-2, and MMP-9 expressions in DRG and their effect lasted for 6 hours, 1 day, 7 days, and 1 day, respectively. By immunofluorescence and Western blotting, there was colocalization of ETAR and MMP-9 in the DRG neurons, whereas MMP-2 was expressed in DRG satellite cells. Furthermore, CGS-26303 treatment also reduced SNL-induced microglia and astrocyte activation on the SDH for 7 days.
  
  
  CONCLUSIONS
  In this study, CGS-26303 can attenuate SNL-induced neuropathic pain by down-regulating MMP-9, MMP-2, and ETAR expressions in the DRG and by glia cell activation in the SDH.
authors.affiliation: Departments of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung.
authors.forename: Hung-Chen
authors.initials: HC
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kuang-I
authors.initials: KI
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chao-Wen
authors.initials: CW
authors.lastname: Chou
authors.affiliation: Department of Neurosurgery, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: m725006@kmu.edu.tw.
authors.forename: Aij-Lie
authors.initials: AL
authors.lastname: Kwan
authors.affiliation: Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: med725006@yahoo.com.tw.
authors.forename: Lin-Li
authors.initials: LL
authors.lastname: Chang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D015536:Down-Regulation; D007278:Injections, Spinal; D008026:Ligation / Q000009:adverse effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism; D009437:Neuralgia / Q000517:prevention & control*; D063065:Organophosphonates / Q000008:administration & dosage* / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves; D013777:Tetrazoles / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000700:Analgesics; D063065:Organophosphonates; D013777:Tetrazoles; C089987:CGS 26303; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Astrocyte; ETAR; MMP-2; MMP-9; Microglia; Neuropathic pain