705: DRG Ischemia Induces Selective Proprioceptive Degeneration Underlying Chronic Postsurgical Leg Pain

Topic: Experimental (Non-clinical) Human Studies
Subtopic: Pain Category (ICD-11), Chronic postsurgical pain, Pain mechanisms (e.g. descending inhibitory control, placebo, inflammation), Pain models (e.g. saline injection, capsaicin, UVB, HFS, incision, exercise, itch), Molecular markers

Background and Aims: Despite successful surgical decompression, 10–40% of patients with lumbar radiculopathy suffer from Chronic Post-Surgical Leg Pain (CPSLP). Our clinical data identifies preoperative foraminal stenosis (FS) as the strongest predictor of this chronicity. We hypothesize that FS creates a unique ischemic watershed within the dorsal root ganglion (DRG) due to its intrinsic vascular architecture. To validate this, we developed a mouse model that recapitulates FS, demonstrating that a chronicity threshold of 30-minute compression is sufficient to induce DRG hypoxia and persistent pain behaviors. This study aims to elucidate the cellular mechanisms linking this transient ischemic stress to long-term proprioceptive dysfunction.

Methods: We established a DRG ischemia–reperfusion (I/R) model by applying a clip to L4 nerve root distal to DRG for 30 minutes, followed by clip release to simulate decompression. Tissue samples were collected at two time points: 24h post-reperfusion to assess acute neuronal vulnerability within DRG, and 3 months at L4 spinal cord segment and soleus muscle to evaluate long-term structural remodeling. Analyses included cleaved Caspase-3 for apoptosis, Hypoxyprobe-1 (pimonidazole HCL) for tissue hypoxia, and subtype characterization with N52, CGRP, and IB4. Muscle spindle morphology was evaluated using PGP9.5, vGLUT1, and GLUT1, and neuronal activation was assessed by c-Fos expression.

Results: Acute analysis at 24 hours revealed a selective vulnerability of neuronal subtypes. Among neurons exhibiting hypoxic stress and apoptotic signaling, large-diameter N52-positive neurons were the predominant population, while CGRP-positive populations were reduced. In the chronic phase at 3 months, animals subjected to prolonged ischemia displayed a significant loss of muscle spindles and severe degeneration of proprioceptive terminals compared to sham and transient ischemia controls. This peripheral degeneration coincided with central maladaptation, as evidenced by sustained spontaneous neuronal hyperexcitability in the superficial dorsal horn, specifically in laminae I–II.

Conclusions: We demonstrate that prolonged nerve root compression initiates a distinct pathogenic cascade in which DRG hypoxia selectively targets vulnerable large-diameter, N52-positive proprioceptive neurons for apoptosis, even after decompression. This acute metabolic legacy leads to progressive degeneration of peripheral proprioceptive terminals in the muscle and maladaptive central sensitization within the spinal cord that ultimately manifests as chronic postsurgical leg pain. These findings identify the duration of ischemic stress, rather than mechanical injury alone, as the critical determinant of surgical failure, suggesting that protecting DRG oxygenation and proprioceptive integrity are essential targets for preventing chronic pain.

References: 1. Alshammari HS, Alshammari AS, Alshammari SA, Ahamed SS. Prevalence of Chronic Pain After Spinal Surgery: A Systematic Review and Meta-Analysis. Cureus 2023;15(7):e41841.
2. Parke WW, Whalen JL. The Vascular Pattern of the Human Dorsal Root Ganglion and Its Probable Bearing on a Compartment Syndrome. Spine 2002;27(4):347-352.
3. Kobayashi S, Yoshizawa H. Effect of mechanical compression on the vascular permeability of the dorsal root ganglion. Journal of Orthopaedic Research 2002;20(4):730-739.
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Presenting Author: Dinh-Thao Trinh
Submitting Author: Dinh Thao Trinh

Senior Author: Jiann-Her Lin

IASP 2026 Global Year theme of Neuropathic Pain: No

• Jiann-Her Lin: PhD, MD - Taipei Medical University