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ATP Release Mechanisms of Endothelial Cell–Mediated Stimulus-Dependent Hyperalgesia

  • Elizabeth K. Joseph
    Affiliations
    Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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  • Paul G. Green
    Affiliations
    Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
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  • Jon D. Levine
    Correspondence
    Address reprint requests to Jon D. Levine, MD, PhD, Departments of Medicine and Oral & Maxillofacial Surgery, University of California at San Francisco, San Francisco, CA 94143-0440.
    Affiliations
    Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
    Search for articles by this author

      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.

      Perspective

      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.

      Key words

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