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Purpose <p>Lumbar intervertebral disc degeneration (IVDD) is characterized by abnormal innervation and neurogenic inflammation, contributing to chronic discogenic pain. Electroacupuncture (EA) alleviates IVDD-related pain, yet its underlying mechanisms remain incompletely understood. This study aimed to investigate the role of the axonal guidance factor Netrin-1 in EA-mediated inhibition of myelinated nerve fiber ingrowth into degenerative intervertebral discs and to elucidate the downstream signaling pathways involved.</p> Methods <p>A rabbit axial compression IVDD model was established. Animals were divided into sham, model, EA, model+OV-Netrin-1, EA+sh-Netrin-1, EA+μ-opioid antagonist (β-FNA), and EA+δ-opioid antagonist (NTI) groups. Tarlov scoring, MRI, HE, AB-PAS, immunohistochemistry, TEM, Western blot, RT-qPCR, Co-IP, ELISA and flow cytometry were used to evaluate disc histology, nerve ingrowth, Netrin-1 expression in annulus fibrosus (AF) and dorsal root ganglion (DRG), endogenous opioid peptides, receptor interactions, cAMP/cGMP levels and intracellular calcium concentration.</p> Results <p>EA improved Tarlov scores, restored disc structure and reduced pathological nerve ingrowth in degenerative discs. EA downregulated Netrin-1 in AF but upregulated Netrin-1 in L2 DRG. DRG Netrin-1 overexpression mimicked EA’s anti-neoinnervation effect, whereas Netrin-1 knockdown abolished EA efficacy. EA elevated spinal POMC/M-ENK; blocking μ/δ opioid receptors reversed EA-mediated Netrin-1 upregulation in DRG. Mechanistically, EA promoted UNC5B-DCC complex formation, reduced cAMP, increased cGMP and lowered intracellular Ca<sup>2+</sup> via Netrin-1 receptors to inhibit myelinated axon sprouting.</p> Conclusion <p>EA upregulates DRG Netrin-1 by activating endogenous opioid peptide signaling. Netrin-1 subsequently modulates UNC5B/DCC downstream cAMP-cGMP-calcium pathways to suppress abnormal myelinated nerve fiber ingrowth, thereby alleviating discogenic pain and delaying IVDD progression.</p>

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Mechanism of Netrin-1 in electroacupuncture-mediated inhibition of nerve fiber ingrowth in degenerative intervertebral discs

  • 期刊论文

  • 发表日期：

    2026年7月4日

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  • Min Wang,
  • Feng Gao,
  • Zixuan Xu,
  • Kaiyang Xue,
  • Yang Yu,
  • Fuwei Wang,
  • Jing Zou,
  • Guofu Huang

摘要

Purpose

Lumbar intervertebral disc degeneration (IVDD) is characterized by abnormal innervation and neurogenic inflammation, contributing to chronic discogenic pain. Electroacupuncture (EA) alleviates IVDD-related pain, yet its underlying mechanisms remain incompletely understood. This study aimed to investigate the role of the axonal guidance factor Netrin-1 in EA-mediated inhibition of myelinated nerve fiber ingrowth into degenerative intervertebral discs and to elucidate the downstream signaling pathways involved.

Methods

A rabbit axial compression IVDD model was established. Animals were divided into sham, model, EA, model+OV-Netrin-1, EA+sh-Netrin-1, EA+μ-opioid antagonist (β-FNA), and EA+δ-opioid antagonist (NTI) groups. Tarlov scoring, MRI, HE, AB-PAS, immunohistochemistry, TEM, Western blot, RT-qPCR, Co-IP, ELISA and flow cytometry were used to evaluate disc histology, nerve ingrowth, Netrin-1 expression in annulus fibrosus (AF) and dorsal root ganglion (DRG), endogenous opioid peptides, receptor interactions, cAMP/cGMP levels and intracellular calcium concentration.

Results

EA improved Tarlov scores, restored disc structure and reduced pathological nerve ingrowth in degenerative discs. EA downregulated Netrin-1 in AF but upregulated Netrin-1 in L2 DRG. DRG Netrin-1 overexpression mimicked EA’s anti-neoinnervation effect, whereas Netrin-1 knockdown abolished EA efficacy. EA elevated spinal POMC/M-ENK; blocking μ/δ opioid receptors reversed EA-mediated Netrin-1 upregulation in DRG. Mechanistically, EA promoted UNC5B-DCC complex formation, reduced cAMP, increased cGMP and lowered intracellular Ca2+ via Netrin-1 receptors to inhibit myelinated axon sprouting.

Conclusion

EA upregulates DRG Netrin-1 by activating endogenous opioid peptide signaling. Netrin-1 subsequently modulates UNC5B/DCC downstream cAMP-cGMP-calcium pathways to suppress abnormal myelinated nerve fiber ingrowth, thereby alleviating discogenic pain and delaying IVDD progression.