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
05/15/2015Pubmed ID
25970319Pubmed Central ID
PMC5070921DOI
10.1097/j.pain.0000000000000224Scopus ID
2-s2.0-84964617156 (requires institutional sign-in at Scopus site) 24 CitationsAbstract
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 DPAuthor
Aaron David Mickle PhD Associate Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCapsaicin
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
