TRPV1 Antagonists and Chronic Pain Beyond Thermal Perception 英文参考文献.docVIP

Pharmaceuticals 2012, 5, 114-132; doi:10.3390/ph5020114 OPEN ACCESS Pharmaceuticals ISSN 1424-8247 /journal/pharmaceuticals Review TRPV1 Antagonists and Chronic Pain: Beyond Thermal Perception Michael R. Brandt 1,2,*, Chad E. Beyer 3 and Stephen M. Stahl 4 1 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA 2 IteraMed L.L.C., Doylestown, PA 18902, USA 3 Ariel Pharmaceuticals, Broomfield, CO 80021 USA; E-Mail: cbeyer@ 4 Neuroscience Education Institute, University of California San Diego, Carlsbad, CA 92008, USA; E-Mail: smstahl@ * Author to whom correspondence should be addressed; E-Mail: brandt.michaelr@; Tel.: +1-908-303-5250. Received: 18 November 2011; in revised form: 18 January 2012 / Accepted: 26 January 2012 / Published: 2 February 2012 Abstract: In the last decade, considerable evidence as accumulated to support the development of Transient Receptor Potential Vanilloid 1 (TRPV1) antagonists for the treatment of various chronic pain conditions. Whereas there is a widely accepted rationale for the development of TRPV1 antagonists for the treatment of various inflammatory pain conditions, their development for indications of chronic pain, where conditions of tactical, mechanical and spontaneous pain predominate, is less clear. Preclinical localization and expression studies provide a firm foundation for the use of molecules targeting TRPV1 for conditions of bone pain, osteoarthritis and neuropathic pain. Selective TRPV1 antagonists weakly attenuate tactile and mechanical hypersensivity and are partially effective for behavioral and electrophysiological endpoints that incorporate aspects of spontaneous pain. While initial studies with TRPV1 antagonist in normal human subjects indicate a loss of warm thermal perception, clinical studies assessing allelic variants suggests that TRPV1 may mediate other sensory modalities under cert