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Degraded myelin is associated with cold hypersensitivity in paclitaxel-induced peripheral neuropathy

Laura R MoraiD, Mary Grace Bishop, Kayleigh Amber RodrigueziD, Dakota M RedlingiD, Renee FoxiD, Ashley M Ezeldin, Emma Zheng, Kimberly StephensiD

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Abstract

Cold allodynia is a debilitating symptom of chemotherapy-induced peripheral neuropathy (CIPN), a side effect of many chemotherapeutics, including paclitaxel (PTX). CIPN is highly prevalent and can lead to cessation of chemotherapy, threatening cancer patient survival. PTX induces cold-evoked pain in 60% of CIPN patients and this pain is a predictor for more severe neuropathy. Cold is transduced by primary sensory neurons in dorsal root ganglia (DRG). PTX can induce maladaptive changes in gene expression that lead to dysregulated nociceptor function. Previous work examining PTX-induced transcriptional changes have been unable to isolate mechanisms associated with pathological cold pain. The epigenetic changes that underlie long- lasting transcriptional changes in PTX-induced persistent cold hypersensitivity are not known. Following three consecutive cycles of PTX, we find that mice continue to exhibit cold hypersensitivity for a minimum of four weeks following the resolution of PTX-induced mechanical hypersensitivity. This exclusive cold hypersensitivity phenotype allows us to examine the mechanisms that specifically underlie pathological cold pain. During this period of PTX-induced cold hypersensitivity, we found decreased expression of genes whose expression is necessary for myelin sheath formation and maintenance, degraded myelin sheaths in the distal sciatic nerve, and decreased chromatin accessibility at genomic regions that contain binding motifs for pro-myelinating transcription factors. Our findings suggest that epigenetic-regulated myelin programs perpetuate myelin degradation and drive pathological cold pain. Our improved understanding of the specific mechanisms that maintain myelin degradation during cold hypersensitivity will improve cold pain management, facilitate the completion of cancer treatment, and improve the quality of life for chronic pain patients.

In-depth summary

Claude Sonnet 4.6 · xhigh effort · 8 Nov 2026 · from the full text of version 2 (7 Oct 2026) · CC BY 4.0

In paclitaxel-treated mice, cold hypersensitivity outlasts mechanical hypersensitivity and coincides with reduced myelin gene expression, lower chromatin accessibility at Egr2/Yy1 motifs, and fragmented sciatic nerve myelin.

Earlier transcriptional work on paclitaxel (PTX) cold pain was confounded by mechanical hypersensitivity, and the epigenetic changes behind persistent cold hypersensitivity were unknown. This mouse model has a window of cold hypersensitivity alone, so dorsal root ganglia (DRG) expression and chromatin accessibility can be profiled in that window.

Key results

  1. ShownAfter three PTX cycles, cold hypersensitivity persisted for at least four weeks after mechanical hypersensitivity returned to baseline, giving a window of exclusive cold hypersensitivity (female mice).

    Mechanical sensitivity returned to baseline on day 114; acetone response stayed elevated to day 141. In the exclusive window, mean response was 11.3±3.4 s (PTX) vs 7.2±2.0 s (vehicle), P=0.0115; AUC 253.9±21.3 vs 129.6±15.8, P<0.0001 (n=8/group). · Consecutive PTX cycles produce persistent cold…; Figure legends

  2. ShownIn DRG during exclusive cold hypersensitivity, bulk RNA-seq showed more downregulated than upregulated genes. Downregulated genes were enriched for myelin assembly, extracellular structure organization, nervous system development and nerve impulse transmission.

    543 differentially expressed genes (FDR<0.05), reported as 173 upregulated and 371 downregulated in PTX vs vehicle (n=4/group). GO and STRING clustering of downregulated genes gave extracellular matrix, myelination, semaphorin-plexin, sodium channel and bleb assembly clusters. · Persistent cold hypersensitivity is associated…; RNA-sequencing and data processing

  3. ShownSciatic nerves of PTX mice had degraded myelin sheaths without a change in axon density, total Mbp, or Iba1+ cell number. Egr2+ cell counts were higher in PTX nerves.

    Full myelin sheaths 26.1±6.3% (PTX) vs 44.2±8.3% (vehicle), P=0.0028; partial sheaths 51.9±4.3% vs 34.7±9.2%, P=0.0044. No difference in axons/µm^2, Mbp/Pgp9.5 ratio or Iba1+ cells; Mbp/Pgp9.5 variance was higher in PTX (n=4/group). · Myelin sheaths in sciatic nerves are degraded…; Figure legends

  4. SuggestedATAC-seq in the same mice found mostly decreased accessibility in PTX DRG. Two regions near downregulated genes (Bcan and Pllp) acted as enhancers in a reporter assay in NIH3T3 cells.

    2095 differentially accessible regions (DARs): 282 more, 1813 less accessible. 63 DARs were annotated to DEGs; 36 were concordant with expression. Luciferase signal 2.030±0.896 and 1.854±0.779 vs 1.000±0.320 for empty vector (P=0.0023 and P=0.0112). · Cold hypersensitivity is associated with…; Figure legends

  5. SuggestedEgr2 and Yy1 binding motifs were enriched in DARs, and most DARs carrying these motifs lost accessibility in PTX mice, including an Egr2-motif region 28 kb from Mbp.

    Of 200 DARs with Egr2 or Yy1 motifs, 90.5% had decreased accessibility in PTX animals and 55% lay in promoter regions (HOMER motif enrichment; n=4/group). · Myelin-regulating transcription factor Egr2 has…; Figure legends

Methods, data and reproducibility

Female C57BL/6J mice received three cycles of PTX or vehicle. Cold and mechanical sensitivity were tracked by acetone and von Frey tests. DRG were profiled by RNA-seq and ATAC-seq, sciatic nerves by immunofluorescence, and two candidate enhancers were tested by luciferase reporter assay.

  • Behavioral testing (acetone and von Frey) of PTX vs vehicle mice · mouse · n = 8 per group
  • DRG bulk RNA-seq (right lumbar L3-7 DRG), PTX vs vehicle · mouse · n = 4 per group (8 libraries)
  • DRG ATAC-seq (left lumbar L3-7 DRG, same mice as RNA-seq), PTX vs vehicle · mouse · n = 4 per group (8 libraries)
  • Sciatic nerve immunofluorescence (Mbp, Pgp9.5, Iba1, Egr2) · mouse · n = 4 per group
  • Luciferase reporter assays of two candidate regulatory regions in NIH3T3 cells · mouse (NIH3T3 line; regions cloned from mouse genomic DNA)
Methods & tools
Trim Galore, FastQC, HISAT2, featureCounts, DESeq2, GOseq, rrvgo, STRING, Bowtie 2, MACS2, DiffBind, HOMER
Reagents & environment
Reads aligned to mouse mm10; ImageJ 2.18.0 and GraphPad Prism 10.4.1 stated. No container or requirements file is mentioned.
Reproducibility gaps
No code is mentioned. Sequencing data are said to be forthcoming via NCBI GEO, with no accession given; all data are otherwise available on reasonable request.
Limitations (5)
  • Bulk RNA-seq of DRG cannot resolve cell-type composition or cell-type-specific expression and chromatin changes; Schwann cell and neuronal subtype contributions remain untested. · stated by the authors
  • The mice were well advanced in adulthood at the time of the exclusive cold hypersensitivity assessments, because of the length of the model. · stated by the authors
  • Myelin was not examined longitudinally across the three PTX cycles, so how resolution of mechanical hypersensitivity relates to myelin damage is unknown. The macrophage and inflammation explanations are hypotheses. · stated by the authors
  • The design is correlative: one late timepoint, female mice only, n=4 per group for omics and histology, with no manipulation of myelin or Egr2 to test a causal link to cold pain. · noted in this summary
  • The DAR threshold is given as P<0.01 in Methods but P<0.001 in the Figure 4 legend. It is a nominal P value without FDR correction, and the DAR counts and the DAR–DEG overlap (63 DARs, 36 concordant) depend on it. · noted in this summary

Read this if you study chemotherapy-induced neuropathy or pain epigenomics and want a mouse model and paired RNA-seq/ATAC-seq design that separates cold from mechanical hypersensitivity.

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