Bone is the most common site of
chronic pain in patients with metastatic
cancer. What remains unclear are the mechanisms that generate this
pain and why
bone cancer pain can be so severe and refractory to treatment with
opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic
tumor cells within the mouse femur,
tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized bone. This
tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked
pain behaviors, an upregulation of
activating transcription factor 3 (ATF3) and
galanin by sensory neurons that innervate the
tumor-bearing femur, upregulation of
glial fibrillary acidic protein (GFAP) and
hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the
tumor-bearing femur. Similar neurochemical changes have been described following
peripheral nerve injury and in other non-cancerous
neuropathic pain states. Chronic treatment with
gabapentin did not influence
tumor growth,
tumor-induced bone destruction or the
tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked
bone cancer-related
pain behaviors. These results suggest that even when the
tumor is confined within the bone, a component of
bone cancer pain is due to
tumor-induced injury to primary afferent nerve fibers that innervate the
tumor-bearing bone.
Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this
chronic pain state.