Intranasal delivery of an antisense oligonucleotide to the RNA-binding protein HuR relieves nerve injury-induced neuropathic pain.

Abstract

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.

• Authors: Vittoria Borgonetti, Nicoletta Galeotti
• Journal: Pain (Pain) Vol. 162 Issue 5 Pg. 1500-1510 (05 01 2021) ISSN: 1872-6623 [Electronic] United States
• PMID: 33259457 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 International Association for the Study of Pain.

Chemical References

• NF-kappa B
• Oligonucleotides, Antisense
• RNA-Binding Proteins

Topics

• Animals
• Hyperalgesia (drug therapy, etiology)
• Mice
• Microglia (metabolism)
• NF-kappa B (metabolism)
• Neuralgia (drug therapy)
• Oligonucleotides, Antisense
• RNA-Binding Proteins
• Spinal Cord (metabolism)