title: Anti-NGF therapy profoundly reduces bone cancer pain and the accompanying increase in markers of peripheral and central sensitization.
abstract: Bone cancer pain can be difficult to control, as it appears to be driven simultaneously by inflammatory, neuropathic and tumorigenic mechanisms. As nerve growth factor (NGF) has been shown to modulate inflammatory and neuropathic pain states, we focused on a novel NGF sequestering antibody and demonstrated that two administrations of this therapy in a mouse model of bone cancer pain produces a profound reduction in both ongoing and movement-evoked bone cancer pain-related behaviors that was greater than that achieved with acute administration of 10 or 30 mg/kg of morphine. This therapy also reduced several neurochemical changes associated with peripheral and central sensitization in the dorsal root ganglion and spinal cord, whereas the therapy did not influence disease progression or markers of sensory or sympathetic innervation in the skin or bone. Mechanistically, the great majority of sensory fibers that innervate the bone are CGRP/TrkA expressing fibers, and if the sensitization and activation of these fibers is blocked by anti-NGF therapy there would not be another population of nociceptors, such as the non-peptidergic IB4/RET-IR nerve fibers, to take their place in signaling nociceptive events.
authors.affiliation: Neurosystems Center and Departments of Preventive Sciences, Psychiatry, Neuroscience, and Cancer Center, University of Minnesota, 515 Delaware Street, Minneapolis, MN 55455, USA.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Sevcik
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Ghilardi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Peters
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Lindsay
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Halvorson
authors.forename: Beth M
authors.initials: BM
authors.lastname: Jonas
authors.forename: Kazufumi
authors.initials: K
authors.lastname: Kubota
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuskowski
authors.forename: Leila
authors.initials: L
authors.lastname: Boustany
authors.forename: David L
authors.initials: DL
authors.lastname: Shelton
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D015415:Biomarkers / Q000378:metabolism; D005266:Femoral Neoplasms / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D020932:Nerve Growth Factor / Q000276:immunology*; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism; D010146:Pain / Q000175:diagnosis / Q000209:etiology* / Q000517:prevention & control*; D010525:Peripheral Nerves / Q000187:drug effects / Q000378:metabolism; D012509:Sarcoma / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D020932:Nerve Growth Factor