ABSTRACT
BACKGROUND: Neuropathic pain is an intractable chronic pain condition caused by damage to the somatosensory system. Although non-coding RNAs such as microRNAs are important regulators of neuropathic pain, the role of long non-coding RNAs (lncRNAs) is poorly understood. METHODS: This study used a rat model of neuropathic pain induced by lumbar fifth spinal nerve ligation (SNL). Microarray analysis of lncRNAs in the lumbar fifth dorsal root ganglion was performed at day 14 after SNL. Expression levels of H19 were examined by using quantitative PCR. In situ hybridization was used to determine the distribution of H19 at day 14 after SNL. Schwann cells were isolated from peripheral nerves at day 14 after SNL. RESULTS: H19 lncRNA was greatly increased in the L5 dorsal root ganglion at day 14 after SNL and was significantly higher at and after day 4. In the dorsal root ganglion, H19 was detected mainly in non-neuronal cells but not in primary sensory neurons. Consistent with this, H19 expression was upregulated in Schwann cells isolated from peripheral nerves after SNL. CONCLUSION: Increased H19 lncRNA in Schwann cells might be involved in neuropathic pain.
Subject(s)
Ganglia, Spinal , Gene Expression , Neuralgia/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Schwann Cells/metabolism , Animals , Chronic Disease , Disease Models, Animal , Ganglia, Spinal/cytology , Ganglia, Spinal/metabolism , Male , Neuralgia/metabolism , Rats, Sprague-Dawley , Real-Time Polymerase Chain ReactionABSTRACT
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 ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1 also known as ß-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.
