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      Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field : Nociceptive TRP channels

      1 , 2
      British Journal of Pharmacology
      Wiley

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          Abstract

          <div class="section"> <a class="named-anchor" id="bph14044-sec-0101"> <!-- named anchor --> </a> <p class="first" id="d306502e198">Control of chronic pain is frequently inadequate and/or associated with intolerable adverse effects, prompting a frantic search for new therapeutics and new therapeutic targets. Nearly two decades of preclinical and clinical research supports the involvement of <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=78" id="d306502e200" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=78</a> in temperature perception, nociception and sensitization. Although there has been considerable excitement around the therapeutic potential of this channel family since the cloning and identification of <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=507" id="d306502e203" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=507</a> cation channels as the <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2486" id="d306502e206" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2486</a> receptor more than 20 years ago, only modulators of a few channels have been tested clinically. TRPV1 channel antagonists have suffered from side effects related to the channel's role in temperature sensation; however, high dose formulations of capsaicin have reached the market and shown therapeutic utility. A number of potent, small molecule antagonists of <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=485" id="d306502e209" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=485</a> channels have recently advanced into clinical trials for the treatment of inflammatory and neuropathic pain, and <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=500" id="d306502e212" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=500</a> antagonists are following closely behind for cold allodynia. <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=509" id="d306502e216" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=509</a>, <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=510" id="d306502e219" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=510</a>, <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=494" id="d306502e222" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=494</a> and <a data-untrusted="" href="http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=495" id="d306502e225" target="xrefwindow">http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=495</a> channels have also been of significant interest. This review discusses the preclinical promise and status of novel analgesic agents that target TRP channels and the challenges that these compounds may face in development and clinical practice. </p> </div><div class="section"> <a class="named-anchor" id="bph14044-sec-0051"> <!-- named anchor --> </a> <h5 class="section-title" id="d306502e229">Linked Articles</h5> <p id="d306502e231">This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit <a data-untrusted="" href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc" id="d306502e233" target="xrefwindow">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc</a> </p> </div>

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          Most cited references171

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          Structure of the TRPV1 ion channel determined by electron cryo-microscopy

          Transient receptor potential (TRP) channels are sensors for a wide range of cellular and environmental signals, but elucidating how these channels respond to physical and chemical stimuli has been hampered by a lack of detailed structural information. Here, we exploit advances in electron cryo-microscopy to determine the structure of a mammalian TRP channel, TRPV1, at 3.4Å resolution, breaking the side-chain resolution barrier for membrane proteins without crystallization. Like voltage-gated channels, TRPV1 exhibits four-fold symmetry around a central ion pathway formed by transmembrane helices S5–S6 and the intervening pore loop, which is flanked by S1–S4 voltage sensor-like domains. TRPV1 has a wide extracellular ‘mouth’ with short selectivity filter. The conserved ‘TRP domain’ interacts with the S4–S5 linker, consistent with its contribution to allosteric modulation. Subunit organization is facilitated by interactions among cytoplasmic domains, including N-terminal ankyrin repeats. These observations provide a structural blueprint for understanding unique aspects of TRP channel function.
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            TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.

            TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.
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              The menthol receptor TRPM8 is the principal detector of environmental cold.

              Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 degrees C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 degrees C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.
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                Author and article information

                Journal
                British Journal of Pharmacology
                British Journal of Pharmacology
                Wiley
                00071188
                June 2018
                June 2018
                November 06 2017
                : 175
                : 12
                : 2185-2203
                Affiliations
                [1 ]Hydra Biosciences; Cambridge MA USA
                [2 ]Clinical Laboratories; Baptist Medical Center; Jacksonville FL USA
                Article
                10.1111/bph.14044
                5980611
                28924972
                4e23d72b-4162-492e-9448-dc23d5498500
                © 2017

                http://doi.wiley.com/10.1002/tdm_license_1.1

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