title: Induction of thermal and mechanical hypersensitivity by parathyroid hormone-related peptide through upregulation of TRPV1 function and trafficking.
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.
authors.affiliation: Department of Pharmacology, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA, USA Department of Anesthesiology, and Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, USA Department of Anesthesia, The University of Iowa Roy J. and Lucile A. Carver College of Medicine, Iowa City, IA, USA (L. Loo is now with the Department of Cell Biology and Physiology, UNC Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA).
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Mickle
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Shepherd
authors.forename: Lipin
authors.initials: L
authors.lastname: Loo
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects; D044162:Parathyroid Hormone-Related Protein / Q000633:toxicity*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000242:Cyclic AMP; D051744:Protein Kinase C-epsilon; D002211:Capsaicin