Combined Anti-inflammatory and Anti-depressant Treatment Reduces Pain and Spinal Cord Nociceptive and Inflammatory Markers in a Rat Discogenic Pain Model

Objective To determine whether a combination therapy targeting spinal inflammation and spinal cord nociceptive and neuroinflammatory processes can improve chronic discogenic pain in a rat model.Design Chronic discogenic pain was induced in male (n=47) and female (n=20) rats with intervertebral disc (IVD) puncture injury. Duloxetine (20 mg/kg, intraperitoneal daily), a serotonin-norepinephrine reuptake inhibitor (SNRI), Etanercept (5 mg/kg, subcutaneous every three days), a tumor necrosis factor-α (TNFα) inhibitor, their combination, or vehicle were delivered 4-weeks post-injury for 2-weeks. Outcomes included hindpaw mechanical hypersensitivity, voluntary locomotion, IVD height and degeneration and immunostaining in the spine and spinal cord (SC) for Substance P (SubP; nociception), glial fibrillary acidic protein (GFAP; neuronal plasticity), TNFα and ionized calcium-binding adapter molecule 1 (Iba1; neuroinflammation). Random-forest regression identified variables associated with pain.Results Injury induced persistent mechanical hypersensitivity, IVD degeneration, spinal inflammation, and increased SC markers. Females exhibited higher baseline SC marker expression than male but responded similarly to combination therapy with improved hindpaw withdrawal thresholds in both sexes (males: Δ=21.08 g, 95% CI: 17.75 to 24.41; females: Δ=20.33 g, 95% CI: 16.90 to 23.76 vs Vehicle). Duloxetine partially improved mechanical pain, and reduced SC markers, while Etanercept selectively reduced TNFα with minimal behavioral improvement. Machine learning analysis identified SC markers as strongly associated with mechanical hypersensitivity. No treatments improved IVD degeneration or spinal inflammation.Conclusions Combined Etanercept and Duloxetine treatment improved pain and reduced spinal cord nociceptive and neuroinflammatory markers, suggesting dual-target pharmacotherapy may be a promising strategy for chronic discogenic pain.