Behavioral signs of pain and functional impairment in a mouse model of osteogenesis imperfecta.
Osteogenesis imperfecta (OI) is a congenital disorder caused most often by dominant mutations in the COL1A1 or COL1A2 genes that encode the alpha chains of type I collagen. Severe forms of OI are associated with skeletal deformities and frequent fractures. Skeletal pain can occur acutely after fracture, but also arises chronically without preceding fractures. In this study we assessed OI-associated pain in the Col1a1Jrt/+ mouse, a recently developed model of severe dominant OI. Similar to severe OI in humans, this mouse has significant skeletal abnormalities and develops spontaneous fractures, joint dislocations and vertebral deformities. In this model, we investigated behavioral measures of pain and functional impairment. Significant hypersensitivity to mechanical, heat and cold stimuli, assessed by von Frey filaments, radiant heat paw withdrawal and the acetone tests, respectively, were observed in OI compared to control wildtype littermates. OI mice also displayed reduced motor activity in the running wheel and open field assays. Immunocytochemical analysis revealed no changes between OI and WT mice in innervation of the glabrous skin of the hindpaw or in expression of the pain-related neuropeptide calcitonin gene-related protein in sensory neurons. In contrast, increased sensitivity to mechanical and cold stimulation strongly correlated with the extent of skeletal deformities in OI mice. Thus, we demonstrated that the Col1a1Jrt/+ mouse model of severe OI has hypersensitivity to mechanical and thermal stimuli, consistent with a state of chronic pain.
Faculty of Dentistry, McGill University, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada.
Dareen M
DM
Abdelaziz
Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada.
Sami
S
Abdullah
Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
Claire
C
Magnussen
Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, QC, Canada.
Alfredo
A
Ribeiro-da-Silva
Faculty of Dentistry, McGill University, Montreal, QC, Canada; Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada.
Svetlana V
SV
Komarova
Shriners Hospitals for Children-Canada and McGill University, Montreal, QC, Canada.
Frank
F
Rauch
Faculty of Dentistry, McGill University, Montreal, QC, Canada; Alan Edwards Centre for Research on Pain, McGill University, Montreal, QC, Canada; Department of Pharmacology & Therapeutics, Faculty of Medicine, McGill University, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada; Department of Anaesthesiology, Faculty of Medicine, McGill University, Montreal, QC, Canada. Electronic address: laura.s.stone@mcgill.ca.
Laura S
LS
Stone
D000700:Analgesics / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D059350:Chronic Pain / Q000503:physiopathology* / Q000628:therapy; D003080:Cold Temperature; D024042:Collagen Type I / Q000235:genetics* / Q000502:physiology; D000090602:Collagen Type I, alpha 1 Chain; D005727:Ganglia, Spinal / Q000473:pathology; D006358:Hot Temperature; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning; D051379:Mice; D009154:Mutation; D009479:Neuropeptides / Q000737:chemistry; D010013:Osteogenesis Imperfecta / Q000188:drug therapy*; D010146:Pain; D059408:Pain Management; D012867:Skin / Q000473:pathology; D013314:Stress, Mechanical; D055114:X-Ray Microtomography
D000700:Analgesics; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D009479:Neuropeptides
Col1a1(Jrt)/+; Collagen mutation; Hypersensitivity; Osteogenesis imperfecta; Pain; Skeletal deformity