Degenerative and regenerative peripheral processes are associated with persistent painful chemotherapy-induced neuropathies in males and females.

This study aimed to investigate the time course of gene expression changes during the progression of persistent painful neuropathy caused by paclitaxel (PTX) in male and female mouse hind paws and dorsal root ganglia (DRG). Bulk RNA-seq was used to investigate the gene expression changes in the paw and DRG collected at 1, 16, and 31 days post-PTX. At these time points, differentially expressed DEGs were predominantly related to reduction or increase in epithelial, skin, bone, and muscle development and to angiogenesis, myelination, axonogenesis, and neurogenesis. These processes were accompanied by regulation of DEGs related to cytoskeleton, extracellular matrix organization and cellular energy production. This gene plasticity during persistent painful neuropathy progression likely represents biological processes linked to tissue regeneration and degeneration. Unlike regeneration/degeneration, gene plasticity related to immune processes was minimal at 1-31 days post-PTX. It was also noted that despite similarities in biological processes and pain chronicity in males and females, specific DEGs showed dramatic sex-dependency. The main conclusions of this study are that gene expression plasticity in paws and DRG during PTX neuropathy progression relates to tissue regeneration and degeneration, minimally affects the immune system processes, and is heavily sex-dependent at the individual gene level.