Abstract: The long-term goal of this project has been to develop a preclinical gene-based therapy for neuropathic pain. Our first step was to utilize a noninvasive peripheral injection of plasmid deoxyribonucleic acid (DNA) complexed with bioabsorbable cationized gelatin (CG) to achieve a nonviral sensory neuron gene transfer. Results establish reporter gene expression in rat lumbar dorsal root ganglia (DRG) 60 hours after retrograde sciatic nerve transport and show that the injection did not cause lasting pain or inflammation. There was no systemic uptake, and off-target gene delivery was limited to the footpad injection site. Increased ipsilateral DRG expression was observed for CG when compared to polyethylenimine, with maximum expression occurring at 7.5:1 CG:DNA ratio under salt-free complexation conditions. Versatility of the injection platform was also demonstrated via plasmid-driven small interfering ribonucleic acid (siRNA)-mediated suppression of glyceraldehyde-3-phosphate dehydrogenase in DRG neurons. In addition to developing a gene transfer strategy, we also investigated the NaV1.8 sodium channel as a potential target for neuropathic pain. In rat models, NaV1.8 is translocated to peripheral axons, which may lead to neuropathic symptomatology. After finding NaV1.8 messenger ribonucleic acid (mRNA) in rat sciatic nerves, we hypothesized that pathology could involve peripheral mRNA increases with subsequent local expression. We found a ∼10-fold increase in sciatic nerve NaV1.8 mRNA in sciatic nerve entrapment (SNE)-injured animals when compared to uninjured and spinal nerve ligation (SNL)-injured animals. There was no difference in NaV.8 polyA tail length between injured and uninjured nerve or DRG NaV1.8, but we found a novel NaV1.8 mRNA variant with a 3' untranslated region shortened by ∼200 bp. This variant was predominant in injured nerve, but not present in uninjured nerve or DRG. The results suggest a mechanistic difference between SNL and SNE models and the presence of a previously undetected species of NaV1.8 mRNA that is upregulated in the periphery after SNE injury. These findings could provide part of a basis for pathological NaV1.8 translocation, additional confirmation of NaV1.8 as a primary molecular target, and in conjunction with the novel gene delivery technology could form a foundation for targeted molecular therapy of neuropathic pain.