Parathyroid Hormone-Related Peptide Elicits Peripheral TRPV1-dependent Mechanical Hypersensitivity

Frontiers in Cellular Neuroscience
Andrew J ShepherdDurga P Mohapatra

Abstract

Bone metastasis in breast, prostate and lung cancers often leads to chronic pain, which is poorly managed by existing analgesics. The neurobiological mechanisms that underlie chronic pain associated with bone-metastasized cancers are not well understood, but sensitization of peripheral nociceptors by tumor microenvironment factors has been demonstrated to be important. Parathyroid hormone-related peptide (PTHrP) is highly expressed in bone-metastasized breast and prostate cancers, and is critical to growth and proliferation of these tumors in the bone tumor microenvironment. Previous studies have suggested that PTHrP could sensitize nociceptive sensory neurons, resulting in peripheral pain hypersensitivity. In this study, we found that PTHrP induces both heat and mechanical hypersensitivity, that are dependent on the pain-transducing transient receptor potential channel family vanilloid, member-1 (TRPV1), but not the mechano-transducing TRPV4 and TRPA1 ion channels. Functional ratiometric Ca2+ imaging and voltage-clamp electrophysiological analysis of cultured mouse DRG neurons show significant potentiation of TRPV1, but not TRPA1 or TRPV4 channel activation by PTHrP. Interestingly, PTHrP exposure led to the slow and sustained ...Continue Reading

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Citations

Aug 8, 2018·Proceedings of the National Academy of Sciences of the United States of America·Andrew J ShepherdDurga P Mohapatra
Jul 14, 2018·Frontiers in Behavioral Neuroscience·Andrew J ShepherdDurga P Mohapatra
May 26, 2018·European Journal of Pain : EJP·A J ShepherdD P Mohapatra
Oct 22, 2018·Current Osteoporosis Reports·Toshiyuki YonedaTatsuo Okui
Oct 19, 2019·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Jia SunDa-Wei Ye
May 28, 2021·Science Translational Medicine·Katelyn E SadlerCheryl L Stucky

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Methods Mentioned

BETA
Transfection
PMA

Software Mentioned

GraphPad
Excel
Prism
pClamp
GraphPad Prism
Clampfit

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