BioProject

Peripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. More...

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. Overall design: From patients with Morton’s neuroma, 22 affected plantar digital nerves were collected during routine surgical excision of the neuroma. From control participants, 11 nerves of the upper and lower limbs were collected (5 nerve grafts, 3 muscle flaps, 3 amputations). We then performed gene expression profiling using bulk RNA-seq to establish transcriptional differences between Morton’s neuroma and control nerves. Less...