ABSTRACT
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.
Subject(s)
Analgesics/administration & dosage , Bone Neoplasms/physiopathology , Pain/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Activating Transcription Factor 3/metabolism , Analysis of Variance , Animals , Behavior, Animal , Bone Neoplasms/drug therapy , Bone and Bones/metabolism , Bone and Bones/pathology , Disease Models, Animal , Disease Progression , Drug Administration Schedule , Functional Laterality , Ganglia, Spinal/metabolism , Gene Expression Regulation, Neoplastic/physiology , Immunohistochemistry/methods , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Nerve Fibers/metabolism , Nerve Fibers/pathology , Pain/etiology , Pain Measurement/methods , TRPV Cation Channels/genetics , TRPV Cation Channels/physiologyABSTRACT
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.
