title: Urinary bladder inflammation induces changes in urothelial nerve growth factor and TRPV1 channels.
abstract: OBJECTIVE
  The urinary bladder urothelium expresses various receptors and in response to chemical and mechanical stimuli releases mediators, thereby modulating bladder sensory pathways. Transient receptor potential vanilloid 1 (TRPV1) ion channels and nerve growth factor (NGF) in those cells are implicated in this modulatory effect and play a role in sensitizing pain-related afferent pathways during inflammation. In this study, we investigated the interaction between NGF and TRPV1 channels in urothelial cells.
  
  
  METHODS
  Urothelial cells from female Sprague-Dawley rat bladders were cultured to quantify membrane expression of TRPV1 channels and capsaicin-induced ATP release in the presence of NGF alone or with TrKA or PI3K inhibitors. Pain scores from rats with cyclophosphamide (CYP)-induced bladder inflammation were assessed after treatment with a TrkA antagonist. Bladders (from control and CYP rats) were collected and analysed for NGF content and TRPV1 channel expression.
  
  
  RESULTS
  Cultured cells responded to NGF with increased TRPV1 channel expression in the cell membrane and increased release of ATP. Both responses were blocked by either a TrkA antagonist or a PI3K inhibitor. Treatment in vivo with the TrkA antagonist alleviated pain symptoms and reduced CYP-induced NGF overexpression in the mucosa. Furthermore, in urothelial cells from animals with bladder inflammation, expression of TRPV1 channels in the membrane was significantly increased.
  
  
  CONCLUSIONS
  During bladder inflammation, increased production of NGF in urothelial cells induced increased expression and activity of TRPV1 channels in the cell membrane. This effect was primarily mediated by the PI3K pathway.
authors.affiliation: Department of Experimental Biology, Faculty of Medicine, University of Porto, Porto, Portugal; Institute for Molecular and Cell Biology (IBMC), University of Porto, Porto, Portugal.
authors.forename: A
authors.initials: A
authors.lastname: Coelho
authors.forename: A S
authors.initials: AS
authors.lastname: Wolf-Johnston
authors.forename: S
authors.initials: S
authors.lastname: Shinde
authors.forename: C D
authors.initials: CD
authors.lastname: Cruz
authors.forename: F
authors.initials: F
authors.lastname: Cruz
authors.forename: A
authors.initials: A
authors.lastname: Avelino
authors.forename: L A
authors.initials: LA
authors.lastname: Birder
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002211:Capsaicin; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D003520:Cyclophosphamide; D003556:Cystitis / Q000139:chemically induced / Q000378:metabolism*; D005260:Female; D020932:Nerve Growth Factor / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000037:antagonists & inhibitors; D050916:TRPV Cation Channels / Q000378:metabolism*; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D002211:Capsaicin; D003520:Cyclophosphamide; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020917:Receptor, trkA; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat