Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture

Juan M. Jimenez-Andrade, Carl D. Martin, Nathan J. Koewler, Katie T. Freeman, Lucy J. Sullivan, Kyle G. Halvorson, Christina M. Barthold, Christopher M. Peters, Ryan J. Buus, Joseph R. Ghilardi, Jack L. Lewis, Michael A. Kuskowski, Patrick W. Mantyh

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

Current therapies to treat skeletal fracture pain are extremely limited. Some non-steroidal anti-inflammatory drugs have been shown to inhibit bone healing and opiates induce cognitive dysfunction and respiratory depression which are especially problematic in the elderly suffering from osteoporotic fractures. In the present report, we developed a closed femur fracture pain model in the mouse where skeletal pain behaviors such as flinching and guarding of the fractured limb are reversed by 10 mg/kg morphine. Using this model we showed that the administration of a monoclonal antibody against nerve growth factor (anti-NGF) reduced fracture-induced pain-related behaviors by over 50%. Treatment with anti-NGF reduced c-Fos and dynorphin up-regulation in the spinal cord at day 2 post-fracture. However, anti-NGF treatment did not reduce p-ERK and c-Fos expression at 20 and 90 min, respectively, following fracture. This suggests NGF is involved in maintenance but not the acute generation of fracture pain. Anti-NGF therapy did not inhibit bone healing as measured by callus formation, bridging of the fracture site or mechanical strength of the bone. As the anti-NGF antibody does not appreciably cross the blood-brain barrier, the present data suggest that the anti-hyperalgesic action of anti-NGF therapy results from blockade of activation and/or sensitization of the CGRP/trkA positive fibers that normally constitute the majority of sensory fibers that innervate the bone. These results demonstrate that NGF plays a significant role in driving fracture pain and that NGF sequestering therapies may be efficacious in attenuating this pain.

Original languageEnglish (US)
Pages (from-to)183-196
Number of pages14
JournalPain
Volume133
Issue number1-3
DOIs
StatePublished - Dec 15 2007
Externally publishedYes

Keywords

  • Bone
  • Monoclonal antibody therapy
  • Nociception
  • Non-malignant skeletal pain
  • Periosteum

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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    Jimenez-Andrade, J. M., Martin, C. D., Koewler, N. J., Freeman, K. T., Sullivan, L. J., Halvorson, K. G., Barthold, C. M., Peters, C. M., Buus, R. J., Ghilardi, J. R., Lewis, J. L., Kuskowski, M. A., & Mantyh, P. W. (2007). Nerve growth factor sequestering therapy attenuates non-malignant skeletal pain following fracture. Pain, 133(1-3), 183-196. https://doi.org/10.1016/j.pain.2007.06.016