Single-nuclei RNA Sequencing Reveals Distinct Transcriptomic Signatures of Rat Dorsal Root Ganglia in a Chronic Discogenic Low Back Pain Model

Abstract

Chronic low back pain (LBP), often correlated with intervertebral disc degeneration, is a leading source of disability worldwide yet remains poorly understood. Current treatments often fail to provide sustained relief, highlighting the need to better understand the mechanisms driving discogenic LBP. During disc degeneration, the extracellular matrix degrades, allowing nociceptive nerve fibers to innervate previously aneural disc regions. Persistent mechanical and inflammatory stimulation of nociceptors can induce plastic changes within dorsal root ganglia (DRG) neurons, characterized by altered gene expression, enhanced excitability, and lowered activation thresholds. Although these transcriptional changes have been described in other pain states, including osteoarthritis, they remain underexplored in discogenic LBP. To address this gap, this study represents the first application of comprehensive single-nuclei RNA sequencing of DRG neurons in a rat model of chronic discogenic LBP. Eighteen distinct DRG subpopulations were identified and mapped to existing mouse and cross-species atlases revealing strong similarities in neuronal populations with the mouse. Differential expression analysis revealed increased expression of pain-associated genes, including Scn9a and Piezo2, and neuroinflammatory mediators such as Fstl1 and Ngfr, in LBP animals. Axial hypersensitivity, measured using grip strength, significantly correlated with increased expression of Scn9a, Fstl1, and Ngfr, which suggests their role in maintaining axial hypersensitivity in this model. These findings establish a relationship between DRG transcriptomic changes and axial hypersensitivity in a discogenic LBP model, identifying potential molecular targets for non-opioid treatments and advancing understanding of discogenic LBP mechanisms.