title: Lycopene ameliorates neuropathic pain by upregulating spinal astrocytic connexin 43 expression.
abstract: OBJECTIVE
  Peripheral nerve injury upregulates tumor necrosis factor (TNF) expression. In turn, connexin 43 (Cx43) expression in spinal astrocytes is downregulated by TNF. Therefore, restoration of spinal astrocyte Cx43 expression to normal level could lead to the reduction of nerve injury-induced pain. While the non-provitaminic carotenoid lycopene reverses thermal hyperalgesia in mice with painful diabetic neuropathy, the antinociceptive mechanism is not entirely clear. The current study evaluated whether the antinociceptive effect of lycopene is mediated through the modulation of Cx43 expression in spinal astrocytes.
  
  
  METHODS
  The effect of lycopene on Cx43 expression was examined in cultured rat spinal astrocytes. The effect of intrathecal lycopene on Cx43 expression and neuropathic pain were evaluated in mice with partial sciatic nerve ligation (PSNL).
  
  
  RESULTS
  Treatment of cultured rat spinal astrocytes with lycopene reversed TNF-induced downregulation of Cx43 protein expression through a transcription-independent mechanism. By contrast, treatment of cultured spinal astrocytes with either pro-vitamin A carotenoid β-carotene or antioxidant N-acetyl cysteine had no effect on TNF-induced downregulation of Cx43 protein expression. In addition, repeated, but not single, intrathecal treatment with lycopene of mice with a partial sciatic nerve ligation significantly prevented not only the downregulation of Cx43 expression in spinal dorsal horn but mechanical hypersensitivity as well.
  
  
  CONCLUSIONS
  The current findings suggest a significant spinal mechanism that mediates the analgesic effect of lycopene, through the restoration of normal spinal Cx43 expression.
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Fang Fang
authors.initials: FF
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan. Electronic address: mnori@hiroshima-u.ac.jp.
authors.forename: Norimitsu
authors.initials: N
authors.lastname: Morioka
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitamura
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Miyauchi
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Yoki
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hisaoka-Nakashima
authors.affiliation: Department of Pharmacology, Hiroshima University Graduate School of Biomedical $_amp_$amp; Health Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nakata
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002338:Carotenoids / Q000494:pharmacology*; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism*; D000077276:Lycopene; D008297:Male; D051379:Mice; D009437:Neuralgia / Q000517:prevention & control*; D051381:Rats; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D018031:Connexin 43; D002338:Carotenoids; D000077276:Lycopene
keywords: Allodynia; Astrocyte; Connexin 43; Lycopene; Neuropathic pain; Nutraceutical; Spinal cord