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.
Ghilardi
Joseph R
JR
Neurosystems Center and Department of Preventive Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Röhrich
Heidi
H
Lindsay
Theodore H
TH
Sevcik
Molly A
MA
Schwei
Matthew J
MJ
Kubota
Kazufumi
K
Halvorson
Kyle G
KG
Poblete
Jeannie
J
Chaplan
Sandra R
SR
Dubin
Adrienne E
AE
Carruthers
Nicholas I
NI
Swanson
Devin
D
Kuskowski
Michael
M
Flores
Christopher M
CM
Julius
David
D
Mantyh
Patrick W
PW
D051700:Activating Transcription Factor 3 / Q000378:metabolism; D000700:Analgesics / Q000008:administration & dosage*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001859:Bone Neoplasms / Q000188:drug therapy / Q000503:physiopathology*; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004334:Drug Administration Schedule; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009412:Nerve Fibers / Q000378:metabolism / Q000473:pathology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010147:Pain Measurement / Q000379:methods; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology
D051700:Activating Transcription Factor 3; D000700:Analgesics; C103002:Atf3 protein, mouse; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse