Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor

Abstract

The number of patients suffering from postoperative pain due to orthopedic surgery and bone fracture is projected to dramatically increase because the human life span, weight, and involvement in high-activity sports continue to rise worldwide. Joint replacement or bone fracture frequently results in skeletal pain that needs to be adequately controlled for the patient to fully participate in needed physical rehabilitation. Currently, the 2 major therapies used to control skeletal pain are nonsteroidal anti-inflammatory drugs and opiates, both of which have significant unwanted side effects. To assess the efficacy of novel therapies, mouse models of orthopedic and fracture pain were developed and evaluated here. These models, orthopedic surgery pain and bone fracture pain, resulted in skeletal pain–related behaviors that lasted 3 weeks and 8 to 10 weeks, respectively. These skeletal pain behaviors included spontaneous and palpation-induced nocifensive behaviors, dynamic weight bearing, limb use, and voluntary mechanical loading of the injured hind limb. Administration of anti–nerve growth factor before orthopedic surgery or after bone fracture attenuated skeletal pain behaviors by 40% to 70% depending on the end point being assessed. These data suggest that nerve growth factor is involved in driving pain due to orthopedic surgery or bone fracture. These animal models may be useful in developing an understanding of the mechanisms that drive postoperative orthopedic and bone fracture pain and the development of novel therapies to treat these skeletal pains.

Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels

“…In other orthopedic surgery animal models (i.e., femoral pin placement and fracture or fracture with casting), spontaneous, palpation-induced nocifensive behaviors and mechanical allodynia were observed (50,51), contrasting our results where mice did not display secondary tactile allodynia after tibial fracture with intramedullary pinning. For example, Guo et al (51) reported mechanical allodynia in rats using von Frey filaments after distal tibial fracture with a cast, but only monitored behavior at a chronic stage (4 wk after surgery).…”

“…For example, Guo et al (51) reported mechanical allodynia in rats using von Frey filaments after distal tibial fracture with a cast, but only monitored behavior at a chronic stage (4 wk after surgery). For nocifensive behavior in a femoral pin placement and fracture model, Majuta et al (50) gently and repeatedly pressed, with thumb and forefinger, the thigh of the fractured hind limb for 2 min. This is different from our protocol of carrying out the von Frey filament test no later than 2 wk after fracture, when the leg is not completely stable (50,52,53).…”

Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain

“…Data is presented as percent weight borne by ipsilateral hindlimb over the total weight borne by both hindlimbs. Dynamic weight bearing was performed as previously described [42; 53; 62]. …”

“…Using this approach we found that anti-P2X3 significantly reduced hypersensitivity of skin, but had no significant effect on attenuating skeletal pain-related behaviors. In contrast, anti-NGF, which has been shown to reduce skeletal pain in both humans and animals models [16; 21; 28; 30; 35; 36; 38; 42; 46; 54; 57], attenuated both mechanical hypersensitivity of the skin and skeletal pain-related behaviors. These results suggest that therapies that attenuate skeletal pain-induced skin hypersensitivity may not always predict therapies that also attenuate the underlying skeletal pain.…”

Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer

“…Both these therapies have also been shown to slow the growth of a wide variety of cancers and are commonly used as a first line therapy to treat CIBP 3,11,21,22,45,48 . Additionally, at least in preclinical models, anti-NGF therapy has also been shown to reduce the growth of head and neck cancer as well as reducing tumor-induced bone remodeling and time to fracture in a mouse model of bone cancer pain 30,52,79,97 .…”