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The Journal of Neuroscience, March 23, 2005, 25(12):3126-3131; doi:10.1523/JNEUROSCI.3815-04.2005

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BRIEF COMMUNICATION
Selective Blockade of the Capsaicin Receptor TRPV1 Attenuates Bone Cancer Pain

Joseph R. Ghilardi,^1,2 Heidi Röhrich,¹ Theodore H. Lindsay,¹ Molly A. Sevcik,¹ Matthew J. Schwei,¹ Kazufumi Kubota,¹ Kyle G. Halvorson,¹ Jeannie Poblete,⁴ Sandra R. Chaplan,⁵ Adrienne E. Dubin,⁵ Nicholas I. Carruthers,⁵ Devin Swanson,⁵ Michael Kuskowski,³ Christopher M. Flores,⁶ David Julius,⁴ and Patrick W. Mantyh^1,2

¹Neurosystems Center and Departments of Preventive Sciences, Psychiatry, Neuroscience, and Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, ²Research Service and ³Geriatric Research, Education, and Clinical Center, Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, ⁴Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143-2140, ⁵Johnson and Johnson Pharmaceutical Research and Development, San Diego, California 92121, and ⁶Johnson and Johnson Pharmaceutical Research and Development, Spring House, Pennsylvania 19446

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.

Key words: tumor; skeletal malignancies; vanilloid receptor; metastasis; nociception; therapy

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Received Sep 14, 2004; revised February 1, 2005; accepted February 1, 2005.

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