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ISSLS Prize Winner: Increased Innervation and Sensory Nervous System Plasticity in a Mouse Model of Low Back Pain Due to Intervertebral Disc Degeneration

Miyagi, Masayuki, MD, PhD*,†,‡,§; Millecamps, Magali, PhD*,†,‡; Danco, Alexander T., MSc*,†,‡,¶; Ohtori, Seiji, MD, PhD§; Takahashi, Kazuhisa, MD, PhD§; Stone, Laura S., PhD*,†,‡,¶,‖,**

doi: 10.1097/BRS.0000000000000334
Basic Science

Study Design. Immunohistochemical and behavioral study using the SPARC (secreted protein, acidic, rich in cysteine)-null mouse model of low back pain (LBP) associated with accelerated intervertebral disc (IVD) degeneration.

Objective. To determine if behavioral signs of LBP in SPARC-null mice are accompanied by sensory nervous system plasticity.

Summary of Background Data. IVD pathology is a significant contributor to chronic LBP. In humans and rodents, decreased expression of SPARC is associated with IVD degeneration. We previously reported that SPARC-null mice exhibit age-dependent behavioral signs of chronic axial LBP and radiating leg pain.

Methods. SPARC-null and age-matched control young, middle-aged, and old mice (1.5, 6, and 24 mo of age, respectively) were evaluated. Cutaneous hind paw sensitivity to cold, heat, and mechanical stimuli were evaluated as measures of radiating pain. The grip force and tail suspension assays were performed to evaluate axial LBP. Motor impairment was assessed using an accelerating rotarod. IVD innervation was identified by immunohistochemistry targeting the nerve fiber marker PGP9.5 and the sensory neuropeptide calcitonin gene-related peptide (CGRP). Sensory nervous system plasticity was evaluated by quantification of CGRP- and neuropeptide-Y-immunoreactivity (-ir) in dorsal root ganglia neurons and CGRP-ir, GFAP-ir (astrocyte marker), and Iba-1-ir (microglia marker) in the spinal cord.

Results. SPARC-null mice developed hypersensitivity to cold, axial discomfort, age-dependent motor impairment, age-dependent increases in sensory innervation in and around the IVDs, age-dependent upregulation of CGRP and neuropeptide-Y in dorsal root ganglia, and age-dependent upregulation of CGRP, microglia, and astrocytes in the spinal cord dorsal horn.

Conclusion. Increased innervation of degenerating IVDs by sensory nerve fibers and the neuroplasticity in sensory neurons and spinal cord could contribute to the underlying pathobiology of chronic discogenic LBP.

Level of Evidence: N/A

SPARC (secreted protein, acidic, rich in cysteine)-null mice show behavioral signs of axial low back pain, radiating leg pain and reduced physical function. Sensory innervation in or near the intervertebral discs, pain-related neuropeptide expression in dorsal root ganglia neurons, and astrocyte and microglia expression in the spinal cord were increased with age and in SPARC-null mice.

*Faculty of Dentistry

Alan Edwards Centre for Research on Pain, and

McGill Scoliosis & Spine Research Group, McGill University, Montreal, Quebec, Canada

§Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Departments of Neurology & Neurosurgery

Anesthesiology and

**Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

Address correspondence and reprint requests to Laura S. Stone, PhD, McGill University, Alan Edwards Centre for Research on Pain, 740 Dr. Penfield Ave, Suite 3200, Montreal, Quebec, Canada H3A 0G1; E-mail address:

Acknowledgment date: October 13, 2013. Revision date: February 11, 2014. Acceptance date: February 12, 2014.

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

A Uehara Memorial Foundation fellowship to Dr. Miyagi, Canadian Institutes for Health Research Operating Grant MOP-102586 to Drs. Stone and Millecamps, a fellowship to Mr. Danco from the McGill University Integrated Program in Neuroscience and Réseau de recherche en santé buccodentainre et osseuse Infrastructure Support to Dr. Stone were received in support of this work.

Relevant financial activities outside the submitted work: grants.

© 2014 by Lippincott Williams & Wilkins