Dynamic transcriptomic profiling of dorsal root ganglia reveals stage-specific mechanisms in diabetic neuropathic pain.

Diabetic peripheral neuropathy (DPN) is the main clinical challenge faced by patients in the middle and advanced stages of diabetes. Due to the unclear cellular and molecular mechanisms, despite decades of in-depth research, its treatment methods are still limited. This study delineates the dynamic transcriptomic landscape of dorsal root ganglia (DRG) in streptozotocin (STZ)-induced diabetic male rats, integrating behavioral phenotyping and cross-model comparisons. We observed phenotypic heterogeneity, with only 60% of STZ-treated rats developing diabetic neuropathic pain (DNP group). In comparison, 37% remained pain-free (non-DNP group) despite comparable hyperglycemia and weight loss. RNA sequencing revealed stage-specific molecular signatures: early DNP (4 weeks post-STZ) involved PI3K-Akt/Ras signaling pathways, whereas late DNP (8 weeks) implicated several virus infection and neuroactive ligand-receptor pathways. Strikingly, 72% of differentially expressed genes (DEGs) at 8 weeks were unique to chronic DNP maintenance. Cross-model analysis demonstrated little overlap between DNP, bone cancer pain, and nerve injury models (<1% shared DEGs), with only Serpina3n universally upregulated. Functional annotations highlighted dysregulated extracellular matrix remodeling, immune receptor activity, and virus-related pathways unique to DNP progression. These findings reveal (1) intrinsic phenotypic variability in diabetic neuropathy progression, (2) temporally distinct pathogenic mechanisms governing DNP initiation versus persistence, and (3) a unique transcriptional fingerprint distinguishing DNP from other neuropathic pain etiologies. This work provides a roadmap for stage-specific therapeutic targeting and underscores the necessity of precision approaches in diabetic neuropathy management.