miR-15b mediates oxaliplatin-induced chronic neuropathic pain through BACE1 down-regulation

  • Br J Pharmacol. 2017 Mar;174(5):386-395. doi: 10.1111/bph.13698.
Naomi Ito  1  2 ,  Atsushi Sakai  1 ,  Noriko Miyake  3 ,  Motoyo Maruyama  1  4 ,  Hirotoshi Iwasaki  1  2 ,  Koichi Miyake  3 ,  Takashi Okada  3 ,  Atsuhiro Sakamoto  2 ,  Hidenori Suzuki  1
Affiliations
  • 1. Department of Pharmacology, Nippon Medical School, Tokyo, Japan.
  • 2. Department of Anesthesiology, Nippon Medical School, Tokyo, Japan.
  • 3. Department of Biochemistry and Molecular Biology, Nippon Medical School, Tokyo, Japan.
  • 4. Division of Laboratory Animal Science, Nippon Medical School, Tokyo, Japan.
PMID: 28012171 DOI: 10.1111/bph.13698
Abstract

Background and purpose: 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.

Experimental approach: 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.

Key results: 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.

Conclusions and implications: These findings suggest that miR-15b contributes to oxaliplatin-induced chronic neuropathic pain at least in part through the down-regulation of BACE1.