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The following is a summary of “Local molecular signature of human peripheral neuropathic pain,” published in the November 2024 issue of Pain by Sandy-Hindmarch et al. 

Focal nerve injuries are commonly associated with neuropathic pain, and although preclinical research suggests neuroimmune signaling involvement, its precise cause in humans remains unclear.  

Researchers conducted a retrospective study to characterize the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton’s neuroma as a human model.  

They compared the cellular and molecular characteristics of individuals with Morton’s neuroma (n = 22; 18 women) to those without nerve injury (n = 11; 4 women). An immunofluorescent staining was applied to examine demyelination and immune cell infiltration, RNA bulk sequencing was performed to identify differentially expressed genes, followed by gene ontology enrichment and weighted gene co-expression network analyses to pinpoint specific molecular modules. Deconvolution analysis was used to evaluate immune cell densities in both groups.  

The results showed that immunofluorescent staining revealed demyelination and immune cell infiltration in Morton’s neuroma, and RNA sequencing identified 3,349 differentially expressed genes between Morton’s neuroma and controls. The gene ontology and weighted gene co-expression network analyses uncovered modules linked to host defense and neurogenesis. Deconvolution analysis confirmed increased macrophage and B cell densities in Morton’s neuroma compared to controls. The immune modules and macrophage populations were associated with individuals’ paroxysmal or evoked pain. A distinct gene signature (MARCO, CD163, STAB1) identified a specific M(GC) macrophage subset, with MARCO gene expression correlating to paroxysmal pain. The targeted immunofluorescent analyses confirmed higher densities of CD163⁺MARCO⁺ macrophages in Morton’s neuroma.  

Investigators concluded the local molecular signature of human focal nerve injury provided a clear evidence of the immune system’s ongoing role in chronic peripheral neuropathic pain, with macrophages, particularly the M(GC) MARCO⁺ subset implicated. 

Source: journals.lww.com/pain/fulltext/9900/the_local_molecular_signature_of_human_peripheral.778.aspx