title: miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down-regulation.
abstract: Although oxaliplatin is an effective anti-cancer platinum compound, it can cause painful chronic neuropathy, and its molecular mechanisms are poorly understood. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression in a sequence-specific manner. Although miRNAs have been increasingly recognized as important modulators in a variety of pain conditions, their involvement in chemotherapy-induced neuropathic pain is unknown.
  
  
  
  Oxaliplatin-induced chronic neuropathic pain was induced in rats by i.p. injections of oxaliplatin (2 mg·kg-1) for five consecutive days. The expression levels of miR-15b and β-site amyloid precursor protein-cleaving enzyme 1 (BACE1 also known as β-secretase 1) were examined in the dorsal root ganglion (DRG). To examine the function of miR-15b, an adeno-associated viral vector encoding miR-15b was injected into the DRG in vivo.
  
  
  
  Among the miRNAs examined in the DRG in the late phase of oxaliplatin-induced neuropathic pain, miR-15b was most robustly increased. Our in vitro assay results determined that BACE1 was a target of miR-15b. BACE1 and miR-15b were co-expressed in putative myelinated and unmyelinated DRG neurons. Overexpression of miR-15b in DRG neurons caused mechanical allodynia in association with reduced expression of BACE1. Consistent with these results, a BACE1 inhibitor dose-dependently induced significant mechanical allodynia.
  
  
  
  These findings suggest that miR-15b contributes to oxaliplatin-induced chronic neuropathic pain at least in part through the down-regulation of BACE1.
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.|Department of Anesthesiology, Nippon Medical School, Tokyo, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Ito
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sakai
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.|Division of Laboratory Animal Science, Nippon Medical School, Tokyo, Japan.
authors.forename: Motoyo
authors.initials: M
authors.lastname: Maruyama
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.|Department of Anesthesiology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Iwasaki
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Miyake
authors.affiliation: Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okada
authors.affiliation: Department of Anesthesiology, Nippon Medical School, Tokyo, Japan.
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D016282:Aspartic Acid Endopeptidases / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005727:Ganglia, Spinal / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009437:Neuralgia / Q000139:chemically induced* / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D009944:Organoplatinum Compounds; C534110:mirn15 microRNA, rat; D000077150:Oxaliplatin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat