title: Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain.
abstract: Skeletal injury is a leading cause of chronic pain and long-term disability worldwide. While most acute skeletal pain can be effectively managed with nonsteroidal anti-inflammatory drugs and opiates, chronic skeletal pain is more difficult to control using these same therapy regimens. One possibility as to why chronic skeletal pain is more difficult to manage over time is that there may be nerve sprouting in nonhealed areas of the skeleton that normally receive little (mineralized bone) to no (articular cartilage) innervation. If such ectopic sprouting did occur, it could result in normally nonnoxious loading of the skeleton being perceived as noxious and/or the generation of a neuropathic pain state. To explore this possibility, a mouse model of skeletal pain was generated by inducing a closed fracture of the femur. Examined animals had comminuted fractures and did not fully heal even at 90+days post fracture. In all mice with nonhealed fractures, exuberant sensory and sympathetic nerve sprouting, an increase in the density of nerve fibers, and the formation of neuroma-like structures near the fracture site were observed. Additionally, all of these animals exhibited significant pain behaviors upon palpation of the nonhealed fracture site. In contrast, sprouting of sensory and sympathetic nerve fibers or significant palpation-induced pain behaviors was never observed in naïve animals. Understanding what drives this ectopic nerve sprouting and the role it plays in skeletal pain may allow a better understanding and treatment of this currently difficult-to-control pain state.
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Stephane R
authors.initials: SR
authors.lastname: Chartier
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Thompson
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Longo
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Michelle N
authors.initials: MN
authors.lastname: Fealk
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Majuta
authors.affiliation: Department of Pharmacology, University of Arizona, Tucson, AZ, USA; Arizona Cancer Center, University of Arizona, Tucson, AZ, USA. Electronic address: pmantyh@email.arizona.edu.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mantyh
mesh_terms: D000320:Adrenergic Fibers / Q000473:pathology* / Q000502:physiology; D000818:Animals; D002113:Calcification, Physiologic / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D059350:Chronic Pain; D004195:Disease Models, Animal; D050723:Fractures, Bone / Q000150:complications* / Q000473:pathology; D019922:GAP-43 Protein / Q000378:metabolism; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059352:Musculoskeletal Pain / Q000209:etiology* / Q000473:pathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D009463:Neuroma / Q000209:etiology / Q000473:pathology; D010147:Pain Measurement; D010173:Palpation / Q000009:adverse effects; D018709:Statistics, Nonparametric; D014965:X-Rays
chemical_list: D019922:GAP-43 Protein; D016900:Neurofilament Proteins; C051774:neurofilament protein H; D015740:Calcitonin Gene-Related Peptide
keywords: Chronic pain; Fracture; Neuropathic; Sensory and sympathetic nerve fibers; Sprouting