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Major differences in transcriptional alterations in dorsal root ganglia between spinal cord injury and peripheral neuropathic pain models

ABSTRACT: Chronic, often intractable pain is caused by neuropathic conditions such as peripheral nerve injury (PNI) and spinal cord injury (SCI). These conditions are associated with alterations in gene and protein expression correlated with functional changes in somatosensory neurons having cell bodies in dorsal root ganglia (DRGs). Most studies of DRG transcriptional alterations have utilized PNI models where axotomy-induced changes important for regeneration may overshadow changes that drive neuropathic pain. Both PNI and SCI produce DRG neuron hyperexcitability linked to pain, but contusive SCI produces little peripheral axotomy or peripheral nerve inflammation. Thus, comparison of transcriptional signatures of DRGs across PNI and SCI models may highlight pain-associated transcriptional alterations that don’t depend on peripheral axotomy and associated effects such as peripheral Wallerian degeneration. Data from our rat thoracic SCI experiments were combined with meta-analysis of whole-DRG RNA-seq datasets from prominent rat PNI models. Striking differences were found between transcriptional responses to PNI and SCI, especially in regeneration-associated genes and long noncoding RNAs. Many transcriptomic changes after SCI were also found after corresponding sham surgery, indicating they were caused by injury to surrounding tissue rather than to the spinal cord itself. Another unexpected finding was of few transcriptomic similarities between any rat neuropathic pain model and the only reported transcriptional analysis of human DRGs linked to neuropathic pain. These findings show that DRGs exhibit complex transcriptional responses to central and peripheral neural and tissue injury. Although few genes in DRG cells show similar changes in gene expression across all these painful conditions, the few widely shared transcriptional alterations promise novel insights into fundamental mechanisms within DRGs that can drive neuropathic pain.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE202111 | GEO | 2022/10/20

REPOSITORIES: GEO

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Project description:Peripheral nerve injury alters the expression of hundreds of proteins in dorsal root ganglia (DRG). Targeting some of these proteins has led to successful treatments for acute pain, but not for sustained postoperative neuropathic pain. The latter may require targeting multiple proteins. Since a single microRNA (miR) can affect the expression of multiple proteins, here, we describe an approach to identify chronic neuropathic pain-relevant miRs. We used two variants of the spared nerve injury (SNI): Sural-SNI and Tibial-SNI and found distinct pain phenotypes between the two. Both models induced strong mechanical allodynia, but only Sural-SNI rats maintained strong mechanical and cold allodynia, as previously reported. In contrast, we found that Tibial-SNI rats recovered from mechanical allodynia and never developed cold allodynia. Since both models involve nerve injury, we increased the probability of identifying differentially regulated miRs that correlated with the quality and magnitude of neuropathic pain and decreased the probability of detecting miRs that are solely involved in neuronal regeneration. We found seven such miRs in L3-L5 DRG. The expression of these miRs increased in Tibial-SNI. These miRs displayed a lower level of expression in Sural-SNI, with four having levels lower than those in sham animals. Bioinformatics analysis of how these miRs could affect the expression of some ion channels supports the view that, following a peripheral nerve injury, the increase of the 7 miRs may contribute to the recovery from neuropathic pain while the decrease of four of them may contribute to the development of chronic neuropathic pain. The approach used resulted in the identification of a small number of potentially neuropathic pain relevant miRs. Additional studies are required to investigate whether manipulating the expression of the identified miRs in primary sensory neurons can prevent or ameliorate chronic neuropathic pain following peripheral nerve injuries. To identify the miRs that were differentially dysregulated between Tibial-SNI and Sural-SNI, we first performed 12 microarrays in a limited number of samples (in four individual DRGs per group: Sham, Tibial-SNI and Sural-SNI; two L3-DRG and two L4-DRG). Then, miRs identified as having differential expression were corroborated with real time qRT-PCR in RNA isolated from individual DRGs (L3, L4 and L5) derived from 4 rats per group (not presented here, but in the manuscript).

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Major differences in transcriptional alterations in dorsal root ganglia between spinal cord injury and peripheral neuropathic pain models

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