REVIEW ARTICLE Anesthesiology 2010; 112:729 – 41 Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins Role of Transient Receptor Potential and Acid-sensing Ion Channels in Peripheral Inflammatory Pain John P. M. White, LL.D.,* Mario Cibelli, M.D.,† Antonio Rei Fidalgo, M.Sc.,‡ Cleoper C. Paule, B.Sc.,‡ Faruq Noormohamed, M.Sc.,* Laszlo Urban, Ph.D.,§ Mervyn Maze, M.B., B.Ch., Istvan Nagy, Ph.D.# ABSTRACT Pain originating in inflammation is the most common pathologic pain condition encountered by the anesthesiologist whether in the con- text of surgery, its aftermath, or in the practice of pain medicine. Inflammatory agents, released as components of the body’s re- sponse to peripheral tissue damage or disease, are now known to be collectively capable of activating transient receptor potential vanilloid type 1, transient receptor potential vanilloid type 4, transient receptor potential ankyrin type 1, and acid-sensing ion channels, whereas individual agents may activate only certain of these ion channels. These ionotropic receptors serve many physiologic functions—as, indeed, do many of the inflammagens released in the inflammatory process. Here, we introduce the reader to the role of these ionotropic receptors in mediating peripheral pain in response to inflammation. I NFLAMMATORY pain describes the pain that is gener- ated by the inflammatory response resulting from wounds, surgical incisions, burn injury, arthritis, infarction, infection, allergic reactions, autoimmune diseases, tumor growth, and other forms of tissue injury or disease. Inflam- mation results in the generation of a plethora of chemical agents that are intended to fight infection and assist in the repair of injured tissue. Unfortunately, the body’s inflamma- tory response to injury, or disease, is ill controlled and is often disproportionate, resulting in pain that is sometimes of such severity that it may hamper recovery or, in the longer term, result in disability. Inflammation commonly results in one, or more, of the three readily recognizable pathologic pain conditions, namely hyperalgesia in which an excessive sensa- tion of pain is elicited by a mild noxious stimulus, such as heat (thermal hyperalgesia) or mechanical pressure (mechani- cal hyperalgesia); allodynia in which pain is elicited by a harm- lesss nonnoxious stimulus; and spontaneous pain in which pain is evoked without any precipitating external stimulus. In cases of severe inflammation, these conditions can inhibit necessary active treatment of the tissue damage. In other cases, the inflammation may not subside, or the pain may persist, notwithstanding the fact that its initiating stimulus has abated, leading to a chronic pain condition. Inflammatory type pain is of immediate concern to anesthe- siologists, because it is an inevitable concomitant of every form of open surgery, the only variables residing in its severity and duration from case to case. Pain of inflammatory origin will also dominate the practice of those anesthesiologists whose specialty is in pain medicine because the overwhelming majority of pathologic pain cases have an inflammatory context of origin. The importance of identifying the role of peripheral mecha- nisms involved in mediating these persistent inflammatory pain conditions resides in the opportunities that such knowledge will provide for facilitating therapeutic interventions to ameliorate these conditions. The mechanisms of nociceptive processing become ever more complex as the signaling, which will ulti- mately be interpreted as pain by the brain, is conveyed from the nerve terminals of primary afferents in the spinal dorsal horn onward toward the brain. Therefore, the most successful therapeu- tic interventions are more likely to arise from developing our under- standing of the peripheral mechanisms of inflammatory pain. Inflammation results in the release of a variety of agents that contribute to alter both the firing pattern of nociceptive primary sensory neurons and nociceptive processing in spinal dorsal horn nociceptive neurons. These include bradykinin, eicosanoids, nerve growth factor (NGF), artemin, glial cell- line-derived neurotrophic factor (GDNF), serotonin, hista- * Research Scientist, ‡ Ph.D. Student,  Sir Ivan Magill Professor of Anaesthetics, # Senior Lecturer, Section of Anaesthetics, Pain Med- icine and Intensive Care, Department of Surgery and Cancer, Impe- rial College London, Chelsea and Westminster Hospital; † Clinical Fellow, Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital; Department of Cardiothoracic Anaesthesia, The Heart Hospital UCLH; and § Executive Director, Preclinical Safety Profiling, Lead Finding Platform, Novartis Insti- tutes for BioMedical Research, Cambridge, Massachusetts. Received from the Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Faculty of Medicine, Chelsea and Westminster Hospital, London, United Kingdom. Submitted for publication November 14, 2008. Accepted for publication October 9, 2009. Support for this work was provided solely from institutional and/or departmental sources. Address correspondence to Dr. Nagy: Section of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Can- cer, Imperial College London Faculty of Medicine Chelsea and Westminster Hospital, Room G3.45, 369 Fulham Road, London SW10 9NH, United Kingdom. i.nagy@imperial.ac.uk. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. ANESTHESIOLO- GY’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. 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