title: ATP release mechanisms of endothelial cell-mediated stimulus-dependent hyperalgesia.
abstract: Endothelin-1 (ET-1) acts on endothelial cells to enhance mechanical stimulation-induced release of adenosine triphosphate (ATP), which in turn can act on sensory neurons innervating blood vessels to contribute to vascular pain, a phenomenon we have referred to as stimulus-dependent hyperalgesia (SDH). In the present study, we evaluated the role of the major classes of ATP release mechanisms to SDH: vesicular exocytosis, plasma membrane-associated ATP synthase, ATP-binding cassette transporters, and ion channels. Inhibitors of vesicular exocytosis (ie, monensin, brefeldin A, and bafilomycin), plasma membrane-associated ATPase (ie, oligomycin and pigment epithelium-derived factor peptide 34-mer), and connexin ion channels (carbenoxolone and flufenamic acid) but not ATP-binding cassette transporter (ie, dipyridamole, nicardipine, or CFTRinh-172) attenuated SDH. This study reports a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes.
  
  
  CONCLUSIONS
  ET-1 acts on endothelial cells to produce mechanical stimulation-induced hyperalgesia. Inhibitors of 3 different ATP release mechanisms attenuated this SDH. This study provides support for a role of ATP in SDH and suggests novel targets for the treatment of vascular pain syndromes.
authors.affiliation: Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Joseph
authors.affiliation: Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Green
authors.affiliation: Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California. Electronic address: Jon.Levine@ucsf.edu.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D019332:Endothelin-1 / Q000009:adverse effects* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000473:pathology; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D018528:ATP-Binding Cassette Transporters; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007473:Ion Channels; D000255:Adenosine Triphosphate
keywords: Endothelin-1; adenosine triphosphate release; endothelium; vascular pain