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

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

doi:10.1016/j.pain.2007.06.016

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Volume 133, Issue 1 , Pages 183-196, 15 December 2007

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

Juan M. Jimenez-Andrade
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Carl D. Martin
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Nathan J. Koewler
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Katie T. Freeman
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Lucy J. Sullivan
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Kyle G. Halvorson
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Christina M. Barthold
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Christopher M. Peters
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
Ryan J. Buus
- Research Service, VA Medical Center, Minneapolis, MN 55417, USA
Joseph R. Ghilardi
- Research Service, VA Medical Center, Minneapolis, MN 55417, USA
Jack L. Lewis
- Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Mechanical Engineering, University of Minnesota, Minneapolis, MN 55455, USA
Michael A. Kuskowski
- GRECC, VA Medical Center, Minneapolis, MN 55417, USA
Patrick W. Mantyh
- Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA
- Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Research Service, VA Medical Center, Minneapolis, MN 55417, USA
- Corresponding author. Address: Neurosystems Center and Department of Diagnostic and Biological Sciences, University of Minnesota, 18-208 Moos Tower, 515 Delaware Street SE, Minneapolis, MN 55455, USA. Tel.: +1 612 626 0180; fax: +1 612 626 2565.

Received 12 February 2007; received in revised form 8 May 2007; accepted 15 June 2007. published online 13 August 2007.

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 10mg/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 90min, 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.