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

• Published in: Pain (Amsterdam) Vol. 133; no. 1-3; pp. 183 - 196
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15.12.2007; Elsevier
• Subjects: Animals; Antibodies - therapeutic use; Antigens, CD - metabolism; Antigens, Differentiation, Myelomonocytic - metabolism; Biological and medical sciences; Bone; Disease Models, Animal; Dynorphins - genetics; Dynorphins - metabolism; Femoral Fractures - complications; Femoral Fractures - diagnostic imaging; Femoral Fractures - etiology; Fundamental and applied biological sciences. Psychology; Illness and personality; Illness, stress and coping; Male; Mice; Mice, Inbred C3H; Monoclonal antibody therapy; Nerve Fibers - metabolism; Nerve Fibers - pathology; Nerve Growth Factors - immunology; Nerve Growth Factors - metabolism; Nociception; Non-malignant skeletal pain; Pain - drug therapy; Pain - etiology; Pain - metabolism; Pain - pathology; Periosteum; Proto-Oncogene Proteins c-fos - genetics; Proto-Oncogene Proteins c-fos - metabolism; Psychology and medicine; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Radiography; Somesthesis and somesthetic pathways (proprioception, exteroception, nociception); interoception; electrolocation. Sensory receptors; Time Factors; Trans-Activators - metabolism; Tyrosine 3-Monooxygenase - metabolism; Up-Regulation - drug effects; Vertebrates: nervous system and sense organs; Nociception; Non-malignant skeletal pain; Bone; Periosteum; Monoclonal antibody therapy; Human; Animal model; Spinal cord; Growth; Central nervous system; Morphine; Opiates; Monoclonal antibody; Neuropeptide; Opioid peptide; Pain; Treatment; Dysfunction; Dynorphin; Behavior; Respiratory depression; Elderly
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2007.06.016

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.