Tackling bone pain at the source: identifying and exploring new therapeutic targets

© 2018 Dr. Sara NenciniPain associated with bone pathology puts a significant burden (both in terms of quality of life and cost) on individuals, society, and the health care system in Australia and worldwide. Current strategies for management are either ineffective or have serious side effect profiles that prohibit use for long-term treatment of bone pain. A major impediment to the development of more targeted strategies is the lack of detailed knowledge of the mechanisms that drive bone pain. To address this, I have developed an exciting, novel in vivo bone-nerve preparation that has been extensively exploited in this thesis to monitor the electrophysiological activity of single sensory neurons that innervate the marrow cavity of the tibial bone of the rat. I provide the first evidence that single sensory neurons that innervate the bone marrow respond to high threshold mechanical stimulation, have response properties consistent with a role in nociception and provide information about different features of an intra-osseous pressure stimulus. These findings show how some bone marrow afferent neurons signal pain in bone diseases and pathologies that involve a mechanical disturbance and/or increased intra-osseous pressure. I have also used this novel in vivo bone-nerve preparation to report roles for a number of growth factors in the pathogenesis of bone pain. In particular, I demonstrate that nerve growth factor (NGF) injected directly into the tibia rapidly activates and sensitizes bone marrow afferent neurons. NGF-induced changes in the activity and sensitivity of bone marrow afferent neurons are dependent on signalling through the TrkA receptor, but are not affected by mast cell stabilization. This provides the conceptual framework for understanding NGF sequestration therapy used to treat inflammatory bone pain. I also report that, in addition to NGF, the Glial cell line-derived neurotrophic factor family ligands (GFLs) (artemin, GDNF, and neurturin), also rapidly activate and sensitize bone afferent neurons, albeit with different time courses. This is exciting because it suggests that some of these GFL signalling pathways could be targeted for the treatment of bone pain. I have further developed and report a new model of carrageenan-induced inflammation of bone to provide evidence that sequestration of artemin reduces inflammation-induced activation and sensitization of bone marrow nociceptors. This provides proof-of-principle that sequestering artemin could be beneficial for the treatment of inflammatory bone pain. Together these results contribute significantly to our understanding of the mechanisms that drive bone pain and have opened the door to opportunities to explore the role of a number of signalling molecules that could be targeted for therapeutic benefit to reduce the significant burden of bone pain