ISSLS prize winner: Increased innervation and sensory nervous system plasticity in a mouse model of low back pain due to intervertebral disc degeneration

Masayuki Miyagi, Magali Millecamps, Alexander T. Danco, Seiji Ohtori, Kazuhisa Takahashi, Laura S. Stone

Research output: Contribution to journalArticlepeer-review

85 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1345-1354
Number of pages10
Issue number17
StatePublished - Aug 1 2014
Externally publishedYes


  • PGP9.5
  • acidic
  • animal model
  • astrocyte
  • axial low back pain
  • calcitonin gene-related peptide
  • disc herniation
  • discogenic low back pain
  • immunohistochemisty
  • innervation
  • intervertebral disc degeneration
  • microglia
  • neuropeptide Y .
  • neuroplasticity
  • radicular pain
  • rich in cysteine (SPARC)
  • secreted protein


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