MicroRNA-182-5p Regulates Nerve Injury-induced Nociceptive Hypersensitivity by Targeting Ephrin Type-b Receptor 1

摘要

Background: The authors and others have previously shown that the up-regulation of spinal ephrin type-b receptor 1 plays an essential role in the pathologic process of nerve injury-induced nociceptive hypersensitivity, but the regulatory mechanism remains unclear. Methods: Radiant heat and von Frey filaments were applied to assess nociceptive behaviors. Real-time quantitative polymerase chain reaction, Western blotting, fluorescence in situ hybridization, immunofluorescence, immunohistochemistry, dual-lucif-erase reporter gene assays, recombinant lentivirus, and small interfering RNA were used to characterize the likely mechanisms. Results: Periphery nerve injury induced by chronic constriction injury of the sciatic nerve significantly reduced spinal microRNA-182-5p (miR-182-5p) expression levels, which were inversely correlated with spinal ephrin type-b receptor 1 expression (R~2 = 0.90; P< 0.05; n = 8). The overexpression of miR-182-5p in the spinal cord prevented and reversed the nociceptive behaviors induced by sciatic nerve injury, accompanied by a decreased expression of spinal ephrin type-b receptor 1 (recombinant lentiviruses containing pre-microRNA-182: 1.91 ±0.34 vs. 1.24±0.31-, n = 4; miR-182-5p mimic: 2.90±0.48 vs. 1.51 ±0.25, n - 4). In contrast, the down-regulation of spinal miR-182-5p facilitated the nociceptive behaviors induced by sciatic nerve injury and increased the expression of spinal ephrin type-b receptor 1 (1.0 ± 0.26 vs. 1.74 ± 0.31, n = 4). Moreover, the down-regulation of miR-182-5p and up-regulation of ephrin type-b receptor 1 caused by sciatic nerve injury were mediated by the N-methyl-D-aspartate receptor. Conclusions: Collectively, our findings reveal that the spinal ephrin type-b receptor 1 is regulated by miR-182-5p in nerve injury-induced nociceptive hypersensitivity.