1. Chapter 83: Bone Cancer and Pain Mary Ann C. Sabino and Denis R. Clohisy

2. Figure 1 Figure 1 Peripheral and central mechanisms of bone cancer. Histophotomicrographs of confocal (A) and histologic (B) serial images of normal bone and confocal images of spinal cord of tumor-bearing mice (D and E). Note the extensive myelinated (gray, NF 200) and unmyelinated (white, CGRP) nerve fibers within bone marrow that appear to course along blood vessels (arrowheads, B). (C) Schematic diagram showing the innervation within periosteum, mineralized bone, and bone marrow. All three tissues may be sensitized during the various stages of bone cancer pain. (D) Confocal imaging of GFAP expressed by astrocytes in a spinal cord of a tumor-bearing mouse. Note increased expression only on side ipsilateral to tumorous limb. (E) High-power magnification of tumor-bearing side of spinal cord showing hypertrophy of astrocytes (white) without changes in neuronal numbers (gray, stained with neuronal marker, NeuN). NF200, neurofilament 200; CGRP, calcitonin gene-related peptide; GFAP, glial fibrillary acidic protein; NeuN, neuronal marker. © 2008 American Society for Bone and Mineral Research From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7 th Edition. www.asbmrprimer.org

3. Figure 2 Figure 2 Interaction between chemical mediators and receptors. Schematic diagram of a peripheral pain fiber expressing receptors and ion channels. Interaction between neurotransmitters and chemical mediators and their cognate receptor results in pain transduction and signaling (Reprinted with permission from Macmillan Publishers Ltd. from Mantyh PW, Clohisy DR, Koltzenburg M, Hunt SP 2002 Molecular mechanisms of cancer pain. Nat Rev Cancer 2:201–209.) H+, protons; ET, endothelin; VR1, vanilloid receptor-1; ETAR, endothelin A receptor; DRASIC, dorsal root acid sensing ion channel; EP, prostaglandin E receptor; PGE2, prostaglandin E2; TrkA, high-affinity nerve growth factor tyrosine kinase receptor A; NGF, nerve growth factor; ATP, adenosine triphosphate; P2X3, purinergic ion-gated receptor; Na+, sodium. © 2008 American Society for Bone and Mineral Research From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7 th Edition. www.asbmrprimer.org