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      Nociceptive TRP Channels: Sensory Detectors and Transducers in Multiple Pain Pathologies

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          Abstract

          Specialized receptors belonging to the transient receptor potential (TRP) family of ligand-gated ion channels constitute the critical detectors and transducers of pain-causing stimuli. Nociceptive TRP channels are predominantly expressed by distinct subsets of sensory neurons of the peripheral nervous system. Several of these TRP channels are also expressed in neurons of the central nervous system, and in non-neuronal cells that communicate with sensory nerves. Nociceptive TRPs are activated by specific physico-chemical stimuli to provide the excitatory trigger in neurons. In addition, decades of research has identified a large number of immune and neuromodulators as mediators of nociceptive TRP channel activation during injury, inflammatory and other pathological conditions. These findings have led to aggressive targeting of TRP channels for the development of new-generation analgesics. This review summarizes the complex activation and/or modulation of nociceptive TRP channels under pathophysiological conditions, and how these changes underlie acute and chronic pain conditions. Furthermore, development of small-molecule antagonists for several TRP channels as analgesics, and the positive and negative outcomes of these drugs in clinical trials are discussed. Understanding the diverse functional and modulatory properties of nociceptive TRP channels is critical to function-based drug targeting for the development of evidence-based and efficacious new generation analgesics.

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          Most cited references214

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          TRP channels.

          The TRP (Transient Receptor Potential) superfamily of cation channels is remarkable in that it displays greater diversity in activation mechanisms and selectivities than any other group of ion channels. The domain organizations of some TRP proteins are also unusual, as they consist of linked channel and enzyme domains. A unifying theme in this group is that TRP proteins play critical roles in sensory physiology, which include contributions to vision, taste, olfaction, hearing, touch, and thermo- and osmosensation. In addition, TRP channels enable individual cells to sense changes in their local environment. Many TRP channels are activated by a variety of different stimuli and function as signal integrators. The TRP superfamily is divided into seven subfamilies: the five group 1 TRPs (TRPC, TRPV, TRPM, TRPN, and TRPA) and two group 2 subfamilies (TRPP and TRPML). TRP channels are important for human health as mutations in at least four TRP channels underlie disease.
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            TRP channels as cellular sensors.

            TRP channels are the vanguard of our sensory systems, responding to temperature, touch, pain, osmolarity, pheromones, taste and other stimuli. But their role is much broader than classical sensory transduction. They are an ancient sensory apparatus for the cell, not just the multicellular organism, and they have been adapted to respond to all manner of stimuli, from both within and outside the cell.
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              Impaired nociception and pain sensation in mice lacking the capsaicin receptor.

              The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Pharmaceuticals (Basel)
                Pharmaceuticals (Basel)
                pharmaceuticals
                Pharmaceuticals
                MDPI
                1424-8247
                14 November 2016
                December 2016
                : 9
                : 4
                : 72
                Affiliations
                [1 ]Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA; amickle@ 123456wustl.edu (A.D.M.); a.shepherd@ 123456wustl.edu (A.J.S.)
                [2 ]Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
                [3 ]Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
                [4 ]Siteman Cancer Center, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO 63110, USA
                Author notes
                [* ]Correspondence: d.p.mohapatra@ 123456wustl.edu ; Tel.: +1-314-362-8229; Fax: +1-314-362-8334
                Article
                pharmaceuticals-09-00072
                10.3390/ph9040072
                5198047
                27854251
                d4bd3907-850c-4a2e-b7d3-ba03f1b283a2
                © 2016 by the authors; licensee MDPI, Basel, Switzerland.

                This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 24 August 2016
                : 09 November 2016
                Categories
                Review

                trp channel,pain,nociception,inflammatory pain,neuropathic pain,visceral pain,cancer pain,migraine,dental pain,peripheral sensitization

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