New advances in musculoskeletal pain

Abstract

Non-malignant musculoskeletal pain is the most common clinical symptom that causes patients to seek medical attention and is a major cause of disability in the world. Musculoskeletal pain can arise from a variety of common conditions including osteoarthritis, rheumatoid arthritis, osteoporosis, surgery, low back pain and bone fracture. A major problem in designing new therapies to treat musculoskeletal pain is that the underlying mechanisms driving musculoskeletal pain are not well understood. This lack of knowledge is largely due to the scarcity of animal models that closely mirror the human condition which would allow the development of a mechanistic understanding and novel therapies to treat this pain. To begin to develop a mechanism-based understanding of the factors involved in generating musculoskeletal pain, in this review we present recent advances in preclinical models of osteoarthritis, post-surgical pain and bone fracture pain. The models discussed appear to offer an attractive platform for understanding the factors that drive this pain and the preclinical screening of novel therapies to treat musculoskeletal pain. Developing both an understanding of the mechanisms that drive persistent musculoskeletal pain and novel mechanism-based therapies to treat these unique pain states would address a major unmet clinical need and have significant clinical, economic and societal benefits.

Fig. 1

Sensory innervation of the mouse bone. A µCT 3D image of a mouse femur illustrating the areas used for analysis of bone innervation (A). Confocal photomicrograph showing CGRP in the mouse femur (B). Low power photomicrograph of the proximal head of the mouse femur where the CGRP-positive (+) fibers are bright white and are present in the marrow and surround the trabeculae (white arrowhead). The inset in the top right of (B) shows the average diameter of individual fibers in a bundle of CGRP fibers found in the marrow. High power photomicrographs of CGRP expressing fiber in the marrow (C) and periosteum (D). Note that the CGRP+ nerve fibers are in close proximity to blood vessels within the Haversian canal system, while in the periosteum CGRP+ nerve fibers form a dense net-like meshwork. Modified from Mach et al. 2002. Neuroscience.

Fig. 2

Representative radiographs showing a naïve, pin and pin+fracture femur in the female and male adult Sprague–Dawley rat. A stainless steel pin was implanted into the intramedullary space of the femur 21 days prior to fracture in order to provide mechanical stability to allow bone healing. Closed mid-diaphyseal fractures of the left femur were produced in female and male rats using a 3-point impactor device. Radiographic images of femurs from naïve (A, B), pin (C, D), and pin+fracture 2 days post-fracture (E, F). Anesthesiology;108(3):473–83, with permission.

Fig. 3

Pain-related behaviors following a closed fracture of the femur in female and male rats. Female and male pin+fracture rats (closed squares) exhibited a greater time spent spontaneously guarding (A, B), a greater number of spontaneous flinches (C, D), and reduced weight bearing of the fractured limb (E, F) as compared to pin rats (open triangles) or age-matched naïve rats (closed circles). There were no differences in pain-related behaviors between female and male rats in nearly all time points. Data are presented as the mean ± standard error of the mean. (*p > 0.05, Bonferroni-adjusted, vs. pin). Anesthesiology;108 (3):473–83, with permission.

Fig. 4

Soft callus formation, which results in stabilization of the fracture site, is shown at day 14 post-fracture by radiographic, micro-computed tomography, and histological analysis. At day 14 post-fracture, calcification of the callus around the fracture site has begun in female and male rats as shown in the radiographs (A, B) and 3D micro-computed tomography images (C, D) of the mid-diaphysis. Additional soft callus formation has occurred at day 14 post-fracture (hematoxylin and eosin) (E, F). This soft callus provides mechanical stabilization of the fractured bone and may in part be responsible for attenuation of acute fracture pain. Scale bar=3.0 mm. Anesthesiology;108(3):473–83, with permission.

Fig. 5

Fracture-induced skeletal pain-related behaviors are significantly attenuated by anti-NGF therapy. Repeated administration of anti-NGF therapy (10 mg/kg; i.p. administered at day 1 and 6 post-fracture) significantly reduced fracture-induced spontaneous (A) and palpation-evoked (B) guarding behavior and number of spontaneous (C) and palpation-evoked flinches (D) at days 2,8, and 12 post-fracture. Note that the anti-NGF anti-nociceptive effect was comparable to or greater than repeated injections (administered 15 min prior to evaluation at day 2, 8, and 12 post-fracture) of 10 mg/kg morphine sulfate (MS). Jimenez-Andrade et al. 2007. Pain. With permission. *p <0.005 vs. fracture+vehicle. #p <0.05 vs. fracture+MS.