Capsaicin-sensitive sensory nerve fibers contribute to the generation and maintenance of skeletal fracture pain

Abstract

Although skeletal pain can have a marked impact on a patient's functional status and quality of life, relatively little is known about the specific populations of peripheral nerve fibers that drive nonmalignant bone pain. In the present report, neonatal male Sprague Dawley rats were treated with capsaicin or vehicle and femoral fracture was produced when the animals were young adults (15-16 weeks old). Capsaicin treatment, but not vehicle, resulted in a significant (>70%) depletion in the density of calcitonin-gene related peptide positive (CGRP + ) sensory nerve fibers, but not 200 kD neurofilament H positive (NF200 + ) sensory nerve fibers in the periosteum. The periosteum is a thin, cellular and fibrous tissue that tightly adheres to the outer surface of all but the articulated surface of bone and appears to play a pivotal role in driving fracture pain. In animals treated with capsaicin, but not vehicle, there was a 50% reduction in the severity, but no change in the time course, of fracture-induced skeletal pain related behaviors as measured by spontaneous flinching, guarding and weight bearing. These results suggest that both capsaicin-sensitive (primarily CGRP + C-fibers) and capsaicin-insensitive (primarily NF200 + A-delta fibers) sensory nerve fibers participate in driving skeletal fracture pain. Skeletal pain can be a significant impediment to functional recovery following trauma-induced fracture, osteoporosis-induced fracture and orthopedic surgery procedures such as knee and hip replacement. Understanding the specific populations of sensory nerve fibers that need to be targeted to inhibit the generation and maintenance of skeletal pain may allow the development of more specific mechanism-based therapies that can effectively attenuate acute and chronic skeletal pain.

Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain

“…Furthermore, we report that in nonhealed fractures with significant nerve sprouting, normally nonnoxious palpation of the bone is now perceived as noxious. As previous data have suggested that the density of sensory inner-vation of the skeleton is correlated to the severity of pain [37,71,72], the present data suggest that the presence of ectopic nerve sprouting in the facture callus, which is the primary load-bearing structure in the nonhealed fracture, may be contributing to use-dependent skeletal pain.…”

Anti–nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery–induced pain

“…The first major problem in measuring pain in rodent preclinical models is that in most cases the behaviors are performed during daylight hours (7am–7pm) which is the time that rodents are normally least active or sleeping [23; 30; 37; 39; 41; 81]. As human clinical trials examining the efficacy of an analgesic on relieving skeletal pain usually focus on when the patient is normally awake, and not when they are sleeping, it is not clear how one can readily translate results obtained from rodents during the time when the animal is least active vs. assessments conducted when humans are normally most active.…”

“…Third, even when “skeletal pain related behaviors” such as limb guarding, flinching or weight bearing are assessed, these behaviors are evoked in that the animal is removed from its home cage during their normal sleep period and their behaviors assessed during the least active period of the animal's day [23; 30; 37; 39; 41; 81]. Equally important, all observer based assessments of pain are subject to unavoidable observer differences and bias [74; 76].…”

Neonatal capsaicin treatment modulates experience‐dependent plasticity in the rat barrel cortex

“…In addition, in a recent study it has been reported that neonatal capsaicin treatment results in depletion of unmyelinated (C-fibers) but not myelinated (Ad fibers) sensory nerve fibers in the periosteum of rats (Jimenez-Andrade et al, 2009). However, neonatal capsaicin treatment can also, albeit to a lesser extent, cause damage to certain Ad fibers.…”