Transcriptomic Evidence for Baclofen Modulation of Inhibitory Synaptic Pathways in Diabetic Neuropathic Pain
This study integrated human transcriptomic reanalysis and mouse models to investigate the molecular mechanisms underlying baclofen's therapeutic effects on diabetic neuropathic pain, focusing on GABAergic dysfunction and
Diabetic neuropathic pain (DNP) represents a significant clinical challenge in metabolic research due to its disabling nature and complex pathophysiology. The condition is characterized by impaired inhibitory neurotransmission and neuroimmune activation, yet the precise molecular mechanisms linking peripheral transcriptomic signatures to central transcriptional alterations remain incompletely understood. Investigating these pathways is critical for developing targeted therapeutic strategies that address both synaptic dysfunction and neuroinflammatory processes in DNP.
The research team employed a multi-faceted approach combining human peripheral blood transcriptomic reanalysis with mouse whole-brain RNA sequencing. Human data from the GSE95849 dataset were utilized to identify immune-inflammatory and synaptic/GABAergic-related signatures through differential expression analysis, custom preranked gene set enrichment analysis (GSEA), and ssGSEA. A streptozotocin-induced DNP mouse model was established, with systemic baclofen treatment administered to evaluate behavioral outcomes including mechanical allodynia, thermal hyperalgesia, grip strength, and motor coordination.
Whole-brain RNA-seq revealed that DNP mice exhibited significant negative enrichment of GABAergic signaling and inhibitory synapse signatures, alongside positive enrichment of neuroinflammation/NF-κB and glial activation-related pathways. Baclofen treatment demonstrated partial and directional modulation of these transcriptional alterations, including a shift toward restoration of inhibitory/synaptic signatures and attenuation of neuroinflammatory pathway activity. RT-qPCR analysis further confirmed that baclofen increased the DNP-suppressed brain expression of Gabra1.
Molecular docking studies supported the preferential interaction of baclofen with the GABAB receptor, including a predicted salt bridge with Arg162 within the Venus Flytrap domain. These findings suggest that GABAB receptor modulation may contribute to restoring inhibitory balance and attenuating neuroinflammatory activation in DNP. The study provides mechanistic evidence for how baclofen alleviates neuropathic hypersensitivity through pathway-level transcriptional changes.
It is important to note that while these findings offer valuable insights into the molecular mechanisms of baclofen's therapeutic effects, they should not be interpreted as clinical recommendations. This research was conducted in a laboratory setting using animal models and human transcriptomic data. The results do not constitute medical advice or product promotion for any specific peptide or pharmaceutical agent. Further studies are required to validate these findings in broader clinical contexts.