Tumor-induced injury of primary afferent sensory nerve fibers in bone cancer pain.

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.

Selective blockade of the capsaicin receptor TRPV1 attenuates bone cancer pain.

Cancer colonization of bone leads to the activation of osteoclasts, thereby producing local tissue acidosis and bone resorption. This process may contribute to the generation of both ongoing and movement-evoked pain, resulting from the activation of sensory neurons that detect noxious stimuli (nociceptors). The capsaicin receptor TRPV1 (transient receptor potential vanilloid subtype 1) is a cation channel expressed by nociceptors that detects multiple pain-producing stimuli, including noxious heat and extracellular protons, raising the possibility that it is an important mediator of bone cancer pain via its capacity to detect osteoclast- and tumor-mediated tissue acidosis. Here, we show that TRPV1 is present on sensory neuron fibers that innervate the mouse femur and that, in an in vivo model of bone cancer pain, acute or chronic administration of a TRPV1 antagonist or disruption of the TRPV1 gene results in a significant attenuation of both ongoing and movement-evoked nocifensive behaviors. Administration of the antagonist had similar efficacy in reducing early, moderate, and severe pain-related responses, suggesting that TRPV1 may be a novel target for pharmacological treatment of chronic pain states associated with bone cancer metastasis.

Bone cancer pain: the effects of the bisphosphonate alendronate on pain, skeletal remodeling, tumor growth and tumor necrosis.

Patients with metastatic breast, lung or prostate cancer frequently have significant bone cancer pain. In the present report we address, in a single in vivo mouse model, the effects the bisphosphonate alendronate has on bone cancer pain, bone remodeling and tumor growth and necrosis. Following injection and confinement of green fluorescent protein-transfected murine osteolytic tumor cells into the marrow space of the femur of male C3H/HeJ mice, alendronate was administered chronically from the time the tumor was established until the bone cancer pain became severe. Alendronate therapy reduced ongoing and movement-evoked bone cancer pain, bone destruction and the destruction of sensory nerve fibers that innervate the bone. Whereas, alendronate treatment did not change viable tumor burden, both tumor growth and tumor necrosis increased. These data emphasize that it is essential to utilize a model where pain, skeletal remodeling and tumor growth can be simultaneously assessed, as each of these can significantly impact patient quality of life and survival.

Different tumors in bone each give rise to a distinct pattern of skeletal destruction, bone cancer-related pain behaviors and neurochemical changes in the central nervous system.

Pain is the most common presenting symptom in patients with bone cancer and bone cancer pain can be both debilitating and difficult to control fully. To begin to understand the mechanisms involved in the generation and maintenance of bone cancer pain, we implanted 3 well-described murine tumor cell lines, 2472 sarcoma, B16 melanoma and C26 colon adenocarcinoma into the femur of immunocompromised C3H-SCID mice. Although each of the tumor cell lines proliferated and completely filled the intramedullary space of the femur within 3 weeks, the location and extent of bone destruction, the type and severity of the pain behaviors and the neurochemical reorganization of the spinal cord was unique to each tumor cell line injected. These data suggest that bone cancer pain is not caused by a single factor such as increased pressure induced by intramedullary tumor growth, but rather that multiple factors are involved in generating and maintaining bone cancer pain.

Simultaneous reduction in cancer pain, bone destruction, and tumor growth by selective inhibition of cyclooxygenase-2.

More than half of all chronic cancer pain arises from metastases to bone, and bone cancer pain is one of the most difficult of all persistent pain states to fully control. Several tumor types including sarcomas and breast, prostate, and lung carcinomas grow in or preferentially metastasize to the skeleton where they proliferate, and induce significant bone remodeling, bone destruction, and cancer pain. Many of these tumors express the isoenzyme cycloxygenase-2 (COX-2), which is involved in the synthesis of prostaglandins. To begin to define the role COX-2 plays in driving bone cancer pain, we used an in vivo model where murine osteolytic 2472 sarcoma cells were injected and confined to the intramedullary space of the femur in male C3HHeJ mice. After tumor implantation, mice develop ongoing and movement-evoked bone cancer pain-related behaviors, extensive tumor-induced bone resorption, infiltration of the marrow space by tumor cells, and stereotypic neurochemical alterations in the spinal cord reflective of a persistent pain state. Thus, after injection of tumor cells, bone destruction is first evident at day 6, and pain-related behaviors are maximal at day 14. A selective COX-2 inhibitor was administered either acutely [NS398; 100 mg/kg, i.p.] on day 14 or chronically in chow [MF. tricyclic; 0.015%, p.o.] from day 6 to day 14 after tumor implantation. Acute administration of a selective COX-2 inhibitor attenuated both ongoing and movement-evoked bone cancer pain, whereas chronic inhibition of COX-2 significantly reduced ongoing and movement-evoked pain behaviors, and reduced tumor burden, osteoclastogenesis, and bone destruction by >50%. The present results suggest that chronic administration of a COX-2 inhibitor blocks prostaglandin synthesis at multiple sites, and may have significant clinical utility in the management of bone cancer and bone cancer pain.

Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain.

Pain is the cancer related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed. A critical question is how closely this model mirrors human bone cancer pain. In the present study we show that, as in humans, pain-related behaviors are diminished by systemic morphine administration in a dose dependent fashion that is naloxone-reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model, the doses of morphine required to block bone cancer pain-related behaviors were ten times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freund's adjuvant (CFA) (1-3mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer vs. inflammatory pain. These results indicate that this model may be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.