Understanding the role of mechanical loading and inflammation in a rodent chronic low back pain model

Chronic low back pain (LBP) and knee osteoarthritis (OA) are the leading causes of disability worldwide. However, current treatments mainly offer temporary relief by managing symptoms rather than addressing the underlying drivers of pain. Both conditions involve mechanical breakdown and inflammation in affected joints, which leads to abnormal nerve ingrowth and increased pain sensitivity. Abnormal nerves extend from cell bodies originating in the dorsal root ganglia (DRG), a peripheral sensory tissue. In healthy intervertebral discs, hydrostatic pressure evenly distributes mechanical forces which maintains structural stability. During degeneration, mechanical force shifts to direct compressive loads, altering tissue mechanics and continuously stimulating innervating nerves. In OA, mechanosensitive ion channels (MSICs) on sensory nerves respond to these abnormal mechanical forces by generating pain signals which leads to sustained nerve activation. Pro-inflammatory cytokines further sensitize MSICs, lowering their activation threshold and amplifying pain. While mechanical loading and inflammation are well-defined contributors to OA, their distinct roles in LBP remain unclear.

Given the shared pathological features of OA and LBP, we hypothesize that activation of MSICs on innervated nerves in degenerated discs drives LBP, with this effect further amplified by inflammation. To test this, we performed single-nuclei RNA sequencing on DRGs from a rat LBP model and analyzed gene expression linked to pain-like behaviors. MSIC (Piezo2) and pro-inflammatory cytokine (IL-6st) were significantly upregulated and trended with increased pain sensitivity in LBP animals, suggesting their roles as central mediators of mechanical pain in LBP. This is the first comprehensive transcriptomic study to correlate DRG gene expression changes with pain-like behaviors in a rat LBP model, providing insight into how mechanical loading may contribute to LBP. Targeting key pain-associated MSICs and pro-inflammatory cytokines may offer new therapeutic approaches for long-term pain relief. Ongoing work is focused on characterizing mechanical and transcriptomic changes in discs from healthy and LBP animals and additional DRG characterization.