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The Molecular Signature of Neuropathic Pain in a Human Model System

ABSTRACT: Peripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. In this multicentre cohort study, we describe the local molecular signature of neuropathic pain at the lesion site, using peripheral nerves of patients with Morton’s neuroma a s a human model system of neuropathic pain. Plantar tibial nerves were collected from 22 patients with Morton's neuroma and control nerves from 11 participants without a nerve injury. Pre-surgery, we collected data on pain severity, duration and nature (e.g., neuropathic pain inventory, NPSI). RNA bulk sequencing of peripheral nerves identified 3349 genes to be differentially expressed between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses (WGCNA) identified over-representation of biological processes related to the inflammatory response, axon guidance and myelination. WGCNA modules specific for the defense and immune responses and neurogenesis. Modules associated with defense response, angiogenesis and muscle system development were correlated with NPSI paroxysmal and evoked pain in Morton’s neuroma patients. Deconvolution analysis confirmed that the densities of M1 and M2 macrophages as well as B-cells were higher in Morton’s neuroma than control samples. The findings for T-cells were inconclusive, and dependent on the reference gene signature used. Immunofluorescent analyses confirmed the presence of demyelination and higher densities of intraneural T-cells in Morton’s neuroma sections compared to control nerves. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250152 | GEO | 2024/07/31

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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The Molecular Signature of Neuropathic Pain in a Human Model System

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