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Induction of thermal and mechanical hypersensitivity by parathyroid hormone-related peptide through upregulation of TRPV1 function and trafficking. Pain 2015 Sep;156(9):1620-1636

Date

05/15/2015

Pubmed ID

25970319

Pubmed Central ID

PMC5070921

DOI

10.1097/j.pain.0000000000000224

Scopus ID

2-s2.0-84964617156 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

The neurobiological mechanisms underlying chronic pain associated with cancers are not well understood. It has been hypothesized that factors specifically elevated in the tumor microenvironment sensitize adjacent nociceptive afferents. We show that parathyroid hormone-related peptide (PTHrP), which is found at elevated levels in the tumor microenvironment of advanced breast and prostate cancers, is a critical modulator of sensory neurons. Intraplantar injection of PTHrP led to the development of thermal and mechanical hypersensitivity in both male and female mice, which were absent in mice lacking functional transient receptor potential vanilloid-1 (TRPV1). The PTHrP treatment of cultured mouse sensory neurons enhanced action potential firing, and increased TRPV1 activation, which was dependent on protein kinase C (PKC) activity. Parathyroid hormone-related peptide induced robust potentiation of TRPV1 activation and enhancement of neuronal firing at mild acidic pH that is relevant to acidic tumor microenvironment. We also observed an increase in plasma membrane TRPV1 protein levels after exposure to PTHrP, leading to upregulation in the proportion of TRPV1-responsive neurons, which was dependent on the activity of PKC and Src kinases. Furthermore, co-injection of PKC or Src inhibitors attenuated PTHrP-induced thermal but not mechanical hypersensitivity. Altogether, our results suggest that PTHrP and mild acidic conditions could induce constitutive pathological activation of sensory neurons through upregulation of TRPV1 function and trafficking, which could serve as a mechanism for peripheral sensitization of nociceptive afferents in the tumor microenvironment.

Author List

Mickle AD, Shepherd AJ, Loo L, Mohapatra DP

Author

Aaron D. Mickle PhD Associate Professor in the Physiology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Capsaicin
Cells, Cultured
Cyclic AMP
Female
Ganglia, Spinal
Humans
Hyperalgesia
Male
Membrane Potentials
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons
Parathyroid Hormone-Related Protein
Protein Kinase C-epsilon
Protein Transport
Receptor, Parathyroid Hormone, Type 1
TRPV Cation Channels
Up-Regulation