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Cytokine Expression in the Epidural Space: A Model of Noncompressive Disc Herniation-Induced Inflammation

Cuéllar, Jason M. MD, PhD*; Borges, Paula M. MD; Cuéllar, Vanessa Gabrovsky MD*; Yoo, Andrew BA*; Scuderi, Gaetano J. MD; Yeomans, David C. PhD§

doi: 10.1097/BRS.0b013e3182604baa
Basic Science

Study Design. Animal study.

Objective. Development of an animal model for the study of biochemical changes that occur in the epidural space after intervertebral disc herniation.

Summary of Background Data. Although strong evidence for an inflammatory component exists, the biochemical processes underlying pain after disc herniation remain unknown.

Methods. Epidural lavage was performed in 48 rats after L5 dorsal root ganglion exposure at baseline and 3, 6, or 24 hours after placement of autologous nucleus pulposus (NP) (N = 15), saline (N = 15), or NP + an interferon-γ antibody (anti-IFN-γ; N = 18) directly onto the dorsal root ganglion. Multiplex assays quantifying interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor α (TNF-α), IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were performed. NP (N = 7) was also analyzed for these cytokines by placing NP into saline and measuring the relative concentration.

Results. Cytokines measured low at baseline (0–100 pg/mL) in all groups. Compared with saline, NP application caused IL-6 elevation, peaking at T = 3 hours, that was prevented by anti-IFN-γ. NP induced elevation of TNF-α, peaking at T = 24 hours and was prevented by anti-IFN-γ. IFN-γ was elevated after NP at T = 3 hours and T = 24 hours. IL-1α was similar after saline versus NP. The concentrations of IL-1β and IL-10 were elevated at T = 3 hours, 6 hours, and 24 hours in all groups without between-groups difference. The level of IL-4 peaked at T = 3 hours in the NP group and was different than saline and NP + anti-IFN-γ groups, but the time effect was insignificant. There was no change for GM-CSF. The concentration of cytokines measured in normal NP was less than 2 pg/mL for all cytokines except TNF-α.

Conclusion. In this model of acute noncompressive disc herniation, NP caused the elevation of epidural IL-6, TNF-α, and IFN-γ—all attenuated by IFN-γ blockade. IL-1β and IL-10 were both significantly elevated by saline alone and their response was not prevented by IFN-γ blockade. This model may prove useful for the study of the biochemical processes by which NP induces inflammation-induced nerve root irritation and radiculopathic pain.

In a new model of herniation of nucleus pulposus (HNP), nucleus pulposus (NP) application to the dorsal root ganglion caused elevation of interleukin (IL)-6, tumor necrosis factor α (TNF-α), interferon-g (IFN-γ), and IL-4. IFN-γ-blockade prevented NP-induced elevation of IL-6, TNF-α, and IFN-γ. Elevation of IL-1β and IL-10 after surgery was not enhanced by NP. IL-6, TNF-α, and IFN-γ may interact during neural root irritation from HNP.

*Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY; and

Departments of Otolaryngology

Orthopaedic Surgery

§Anesthesia, Stanford University School of Medicine, Stanford, CA.

Address correspondence and reprint requests to Jason M. Cuéllar, MD, PhD, Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, 301 East 17th St., New York, NY 10003; E-mail:

Acknowledgment date: March 2, 2012. First revision date: May 14, 2012. Acceptance date: May 17, 2012.

The manuscript submitted does not contain information about medical device(s)/drug(s).

No funds were received in support of this work.

One or more of the author(s) has/have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript: e.g., honoraria, gifts, consultancies, royalties, stocks, stock options, decision-making position.

© 2013 Lippincott Williams & Wilkins, Inc.