Fracture-induced pain-like behaviours in a femoral fracture mouse model

Abstract

Summary This study is the first comprehensive characterisation of the pain phenotype after fracture using both evoked and naturalistic behaviours in adult male and ovariectomised female mice. It also shows that an anti-nerve growth factor (NGF) therapy could be considered to reduce pain after fracture surgery. Introduction Bone fractures are common due to the ageing population and very painful even after healing. The phenotype of this pain is still poorly understood. We aimed to characterise it in a femoral fracture model in mice. Methods We employed both adult male, and female ovariectomised (OVX) mice to mimic osteoporotic fractures. Mice underwent a unilateral femoral fracture maintained by an external fixator or a sham surgery. Pain behaviours, including mechanical and thermal sensitivity, weight bearing and LABORAS, were measured from baseline to 6 weeks after fracture. The effect on pain of an antibody against nerve growth factor (anti-NGF) was assessed. Changes in nerve density at the fracture callus were analysed by immunohistochemistry. Results Following surgery, all groups exhibited high levels of invoked nociception. Mechanical and thermal hyperalgesia were observed from 1 week after surgery, with nociceptive sensitization in the fracture group maintained for the 6 weeks, whereas it resolved in the sham group after 3 weeks. OVX induced reduction in pain thresholds, which was maintained after fracture. The frequency of naturalistic behaviours did not change between groups. Anti-NGF administered before and weekly after surgery alleviated fracture-induced mechanical nociception. The density of nerve fibres in the fracture callus was similar in all groups 6 weeks after surgery. Conclusions Fractures in rodent models are highly painful in both sexes. This pain-like phenotype is prolonged and should be routinely considered in fracture healing studies as it can affect the study outcome. The anti-NGF alleviates fracture-induced mechanical pain.

A Buprenorphine depot formulation provides effective sustained post-surgical analgesia for 72h in mouse femoral fracture models

“…reported mechanical hyperalgesia and cold sensitivity in male mice after sham surgery (no external fixator and osteotomy) and femur fracture over 6 weeks while the sham group significantly improved after 3 weeks (Magnusdottir et al, 2021). This indicates that the wound healing itself already plays an important role in potential pain sensitization after osteotomy.…”

“…Due to the functional impairment, limping as well as changes in gait parameters after osteotomy are expected as a mixture of residual pain due to local inflammatory processes and periosteal pain as well as the restricted functionality of the femur. Magnusdottir et al reported mechanical hyperalgesia and cold sensitivity in male mice after sham surgery (no external fixator and osteotomy) and femur fracture over 6 weeks while the sham group significantly improved after 3 weeks (Magnusdottir et al, 2021). This indicates that the wound healing itself already plays an important role in potential pain sensitization after osteotomy.…”

What Did We Learn About Fracture Pain from Animal Models?

“… 45 This model was recently used to study pain behaviours after fracture. 46 In this model, the pain-like phenotype was maintained 6 weeks after fracture surgery.…”

Chronic Pain after Bone Fracture: Current Insights into Molecular Mechanisms and Therapeutic Strategies

“…On the basis of the fracture model, the osteoporotic fracture model was developed to study another common fracture in clinical practice, the osteoporotic fracture [ 17 ]. This model is mostly made in female mice (because osteoporosis is more common in postmenopausal women).…”