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TNF-α and Phosphorylation of ERK in DRG and Spinal Cord: Insights Into Mechanisms of Sciatica

Takahashi, Naoto, MD, PhD; Kikuchi, Shinichi, MD, PhD§; Shubayev, Veronica I., MD*‡; Campana, W Marie, PhD*; Myers, Robert R., PhD*†‡

doi: 10.1097/01.brs.0000201305.01522.17
Basic Science

Study Design. Characterize extracellular signal-regulated kinase (ERK) and its phosphorylation (pERK) in neural tissues after topical application of tumor necrosis factor-alpha (TNF-α) to L5 nerve root.

Objective. Identify time-course, localization, and expression of pERK.

Summary of Background Data. TNF-α has a key role in disc herniation and sciatica as an inflammatory component of the nucleus pulposus. ERK is associated with neuronal signal transduction and nociception.

Methods. We studied tissue from naive rats, vehicle-treated rats, and rats receiving rat recombinant TNF-α using Western blots of total and phosphorylated ERK (pERK). We used immunohistochemistry of pERK with neuronal nuclear (NeuN) antibody to identify its cellular distribution.

Results. Topical application of TNF-α to rat nerve root increased pERK in ipsilateral dorsal root ganglion (DRG) neurons and glia within 5 hours. pERK was not expressed in DRG during the first hour after TNF-α application, nor was it seen at anytime in spinal cord dorsal horn. DRG satellite cells had increased pERK 5 hours after TNF-α or vehicle treatment. TNF-α treatment increased pERK in small- and medium-sized DRG neurons and to a lesser degree in large neurons.

Conclusions. These findings suggest that ERK signaling plays a role in the activation of DRG cells following inflammatory injuries to nerve roots and further documents the importance of inflammation in the pathogenesis of painful spine disorders.

Tumor necrosis factor-α-induced neuronal inflammation is a key aspect of painful spinal disease. We characterized dorsal root ganglion neuronal and glial phosphorylation of extracellular signal-regulated kinase following topical application of tumor necrosis factor alpha to rat nerve root. Since phosphorylated extracellular signal-regulated kinase-associated signal transduction is closely linked to nociception, these data suggest that tumor necrosis factor alpha application without compression may be painful.

From the *Department of Anesthesiology, University of California, San Diego School of Medicine, San Diego, CA; †Department of Pathology, University of California, San Diego School of Medicine; San Diego, CA; ‡VA San Diego Healthcare System, La Jolla, CA; and §Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.

Acknowledgment date: December 8, 2004. First revision date: February 28, 2005. Acceptance date: March 17, 2005.

Supported in part by NIH Grant No. NS18715 and the Department of Veterans Affairs.

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

Federal funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.

Address correspondence and reprint requests to Robert Myers, PhD, Department of Anesthesiology (0629), University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0629. E-mail:

© 2006 Lippincott Williams & Wilkins, Inc.