神经病理性疼痛
小胶质细胞
基因敲除
鼻腔给药
医学
促炎细胞因子
脊髓
p38丝裂原活化蛋白激酶
基因沉默
MAPK/ERK通路
分子生物学
癌症研究
化学
信号转导
药理学
免疫学
细胞生物学
生物
炎症
细胞凋亡
基因
生物化学
精神科
作者
Vittoria Borgonetti,Nicoletta Galeotti
出处
期刊:Pain
[Lippincott Williams & Wilkins]
日期:2020-11-30
卷期号:162 (5): 1500-1510
被引量:43
标识
DOI:10.1097/j.pain.0000000000002154
摘要
Abstract Neuropathic pain remains an undertreated condition and there is a medical need to develop effective treatments. Accumulating evidence indicates that posttranscriptional regulation of gene expression is involved in neuropathic pain; however, RNA processing is not clearly investigated. Our study investigated the role of HuR, an RNA binding protein, in promoting neuropathic pain and trauma-induced microglia activation in the spared nerve injury mouse model. To this aim, an antisense oligonucleotide (ASO) knockdown of HuR gene expression was used. Antisense oligonucleotides poorly cross the blood–brain barrier and an intranasal (i.n.) administration was used to achieve central nervous system penetration through a noninvasive delivery. The efficacy of i.n. ASO administration was compared to an intrathecal (i.t.) delivery. I.n. administered ASO reduced spinal HuR protein and relieved pain hypersensitivity with a similar efficacy to i.t. administration. Immunofluorescence studies showed that HuR was expressed in activated microglia, colocalized with p38 and, partially, with extracellular signal-regulated kinase (ERK)1/2 within the spinal cord dorsal horn. An anti-HuR ASO inhibited the activation of spinal microglia by reducing the levels of proinflammatory cytokines, inducible nitric oxide synthase, the activation of nuclear factor-κB (NF-κB), and suppressed the spared nerve injury–induced overphosphorylation of spinal p38, ERK1/2 and c-Jun-N-terminal kinase (JNK)-1. In addition, HuR silencing increased the expression of the anti-inflammatory cytokine IL-10, promoting the shift of microglial M1 to M2 phenotype. Targeting HuR by i.n. anti-HuR ASO might represent a noninvasive promising perspective for neuropathic pain management by its powerful inhibition of microglia-mediated spinal neuroinflammation and promotion of an anti-inflammatory and neuroprotectant response.
科研通智能强力驱动
Strongly Powered by AbleSci AI