Abstract
Pain is associated with most bony pathologies. Clinical and experimental observations suggest that bone pain can be derived from noxious stimulation of the periosteum or bone marrow. Sensory neurons are known to innervate the periosteum and marrow cavity, and most of these have a morphology and molecular phenotype consistent with a role in nociception. However, little is known about the physiology of these neurons, and therefore information about mechanisms that generate and maintain bone pain is lacking. The periosteum has received greater attention relative to the bone marrow, reflecting the easier access of the periosteum for experimental assessment. With the electrophysiological preparations used, investigators have been able to record from single periosteal units in isolation, and there is a lot of information available about how they respond to different stimuli, including those that are noxious. In contrast, preparations used to study sensory neurons that innervate the bone marrow have been limited to recording multi-unit activity in whole nerves, and whilst they clearly report responses to noxious stimulation, it is not possible to define responses for single sensory neurons that innervate the bone marrow. There is only limited evidence that peripheral sensory neurons that innervate bone can be sensitized or that they can be activated by multiple stimulus types, and at present this only exists in part for periosteal units. In the central nervous system, it is clear that spinal dorsal horn neurons can be activated by noxious stimuli applied to bone. Some can be sensitized under pathological conditions and may contribute in part to secondary or referred pain associated with bony pathology. Activity related to stimulation of sensory nerves that innervate bone has also been reported in neurons of the spinoparabrachial pathway and the somatosensory cortices, both known for roles in coding information about pain. Whilst these provide some clues as to the way information about bone pain is centrally coded, they need to be expanded to further our understanding of other central territories involved. There is a lot more to learn about the physiology of peripheral sensory neurons that innervate bone and their central projections.
Highlights
This review aims to summarize and critically evaluate our current understanding of the physiological properties of peripheral sensory neurons that innervate bone, and how information about noxious stimulation coded by these neurons is passed through the central nervous system to the cerebral cortex to elicit painful sensations
They reported increased spontaneous activity and reduced heat thresholds in peripherally recorded C fiber afferents in animals that had developed behavioral sensitivity in response to injection of tumor cells in and around the calcaneus, but not in control animals. In both of these studies, the tumor cells were not clearly confined to the bone, and the C fibers recorded were cutaneous afferents, and so the sensitization was not of bone afferent neurons, but rather of cutaneous afferent neurons innervating the surrounding skin. These studies are more relevant to an understanding of secondary or referred pain associated with bony pathology than the pain perceived on stimulation of the bone itself
There are many studies that have reported the existence of sensory neurons that innervate the periosteum and marrow cavity, and it has become clear that most of these have a morphology and molecular phenotype consistent with a role in nociception
Summary
This review aims to summarize and critically evaluate our current understanding of the physiological properties of peripheral sensory neurons that innervate bone, and how information about noxious stimulation coded by these neurons is passed through the central nervous system to the cerebral cortex to elicit painful sensations. Other agents that inhibit the activity of osteoclasts (e.g., Osteoprotegerin) or that act by reducing inflammatory processes (e.g., function blocking nerve growth factor antibodies) produce significant analgesia in animal models of bone cancer-induced and fracture pain (Honore et al, 2000a; Halvorson et al, 2005; Sevcik et al, 2005; JimenezAndrade et al, 2007; Koewler et al, 2007) These primarily exert effects in the periphery and are targeted at the causes of bone pain. Patients with bone cancer often report another more intense pain upon movement or weight-bearing (breakthrough pain) (Portenoy et al, 1999) It appears that both the periosteum and the marrow cavity of bones must be innervated by primary afferent neurons capable of transducing and transmitting nociceptive information. Many experimental studies reporting pain behavior in animal models of bony pathology use behavioral testing platforms that assay pain, thermal or mechanical sensitivity primarily (or exclusively) at skin around the affected bone (Cain et al, 2001; Urch et al, 2003; Yanagisawa et al, 2010; Uhelski et al, 2013), and so are likely to monitor mechanisms associated with secondary or referred pain, not primary pain associated with direct stimulation of nociceptors in bone
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
