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Ion Channel Pharmacology for Pain Modulation

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Concepts and Principles of Pharmacology

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 260))

Abstract

A large series of different ion channels have been identified and investigated as potential targets for new medicines for the treatment of a variety of human diseases, including pain. Among these channels, the voltage gated calcium channels (VGCC) are inhibited by drugs for the treatment of migraine, neuropathic pain or intractable pain. Transient receptor potential (TRP) channels are emerging as important pain transducers as they sense low pH media or oxidative stress and other mediators and are abundantly found at sites of inflammation or tissue injury. Low pH may also activate acid sensing ion channels (ASIC) and mechanical forces stimulate the PIEZO channels. While potent agonists of TRP channels due to their desensitizing action on pain transmission are used as topical applications, the potential of TRP antagonists as pain therapeutics remains an exciting field of investigation. The study of ASIC or PIEZO channels in pain signaling is in an early stage, whereas antagonism of the purinergic P2X3 channels has been reported to provide beneficial effects in chronic intractable cough. The present chapter covers these intriguing channels in great detail, highlighting their diverse mechanisms and broad potential for therapeutic utility.

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References

  • Abbracchio MP, Burnstock G (1994) Purinoceptors: are there families of P2X and P2Y purinoceptors? Pharmacol Ther 64(3):445–475

    Article  CAS  PubMed  Google Scholar 

  • Abdulqawi R, Dockry R, Holt K, Layton G, Mccarthy BG, Ford AP, Smith JA (2015) P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study. Lancet 385(9974):1198–1205

    Article  CAS  PubMed  Google Scholar 

  • Akopian AN, Chen CC, Ding Y, Cesare P, Wood JN (2000) A new member of the acid-sensing ion channel family. Neuroreport 11(10):2217–2222

    Article  CAS  PubMed  Google Scholar 

  • Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci 28(5):1046–1057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alvarez de la Rosa D, Krueger SR, Kolar A, Shao D, Fitzsimonds RM, Canessa CM (2003) Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J Physiol 546(Pt 1):77–87

    Article  CAS  PubMed  Google Scholar 

  • Andersson DA, Gentry C, Moss S, Bevan S (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28(10):2485–2494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andrews MD, Af Forselles K, Beaumont K, Galan SR, Glossop PA, Grenie M et al (2015) Discovery of a selective TRPM8 antagonist with clinical efficacy in cold-related pain. ACS Med Chem Lett 6(4):419–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antoniazzi CTD, Nassini R, Rigo FK, Milioli AM, Bellinaso F, Camponogara C et al (2019) Transient receptor potential ankyrin 1 (TRPA1) plays a critical role in a mouse model of cancer pain. Int J Cancer 144(2):355–365

    Article  CAS  PubMed  Google Scholar 

  • Arsenault P, Chiche D, Brown W, Miller J, Treister R, Leff R et al (2018) NEO6860, modality-selective TRPV1 antagonist: a randomized, controlled, proof-of-concept trial in patients with osteoarthritis knee pain. Pain Rep 3(6):e696

    Article  PubMed  PubMed Central  Google Scholar 

  • Baconguis I, Gouaux E (2012) Structural plasticity and dynamic selectivity of acid-sensing ion channelspider toxin complexes. Nature 489(7416):400–405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baconguis I, Bohlen CJ, Goehring A, Julius D, Gouaux E (2014) X-ray structure of acid-sensing ion channel 1-snake toxin complex reveals open state of a Na(+)-selective channel. Cell 156(4):717–729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bang S, Kim KY, Yoo S, Kim YG, Hwang SW (2007) Transient receptor potential A1 mediates acetaldehyde-evoked pain sensation. Eur J Neurosci 26(9):2516–2523

    Article  PubMed  Google Scholar 

  • Bannister RA, Beam KG (2013) Ca(V)1.1: the atypical prototypical voltage-gated Ca(2)(+) channel. Biochim Biophys Acta 1828(7):1587–1597

    Article  CAS  PubMed  Google Scholar 

  • Barclay J, Patel S, Dorn G, Wotherspoon G, Moffatt S, Eunson L et al (2002) Functional downregulation of P2X3 receptor subunit in rat sensory neurons reveals a significant role in chronic neuropathic and inflammatory pain. J Neurosci 22(18):8139–8147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bauer CS, Nieto-Rostro M, Rahman W, Tran-Van-Minh A, Ferron L, Douglas L, Dolphin AC (2009) The increased trafficking of the calcium channel subunit alpha2delta-1 to presynaptic terminals in neuropathic pain is inhibited by the alpha2delta ligand pregabalin. J Neurosci 29(13):4076–4088

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baumann TK, Chaudhary P, Martenson ME (2004) Background potassium channel block and TRPV1 activation contribute to proton depolarization of sensory neurons from humans with neuropathic pain. Eur J Neurosci 19:1343–1351

    Article  Google Scholar 

  • Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL et al (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448(7150):204–208

    Article  CAS  PubMed  Google Scholar 

  • Benson CJ, Xie J, Wemmie JA, Price MP, Henss JM, Welsh MJ, Snyder PM (2002) Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc Natl Acad Sci U S A 99(4):2338–2343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhattacharya MR, Bautista DM, Wu K, Haeberle H, Lumpkin EA, Julius D (2008) Radial stretch reveals distinct populations of mechanosensitive mammalian somatosensory neurons. Proc Natl Acad Sci U S A 105(50):20015–20020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Blau JN, Engel HO (2004) Individualizing treatment with verapamil for cluster headache patients. Headache 44(10):1013–1018

    Article  PubMed  Google Scholar 

  • Boland LM, Morrill JA, Bean BP (1994) Omega-conotoxin block of N-type calcium channels in frog and rat sympathetic neurons. J Neurosci 14(8):5011–5027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bonet IJM, Fischer L, Parada CA, Tambeli CH (2013) The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia. Neuropharmacology 65:206–212

    Article  CAS  PubMed  Google Scholar 

  • Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12(4–5):256–268

    Article  CAS  PubMed  Google Scholar 

  • Broad LM, Mogg AJ, Eberle E, Tolley M, Li DL, Knopp KL (2016) TRPV3 in drug development. Pharmaceuticals (Basel) 9(3):55

    Article  CAS  Google Scholar 

  • Brockway LM, Zhou Z-H, Bubien JK, Jovov B, Benos DJ, Keyser KT (2002) Rabbit retinal neurons and glia express a variety of ENaC/DEG subunits. Am J Physiol Cell Physiol 283(1):C126–C134

    Article  CAS  PubMed  Google Scholar 

  • Bussone G, Leone M, Peccarisi C, Micieli G, Granella F, Magri M et al (1990) Double blind comparison of lithium and verapamil in cluster headache prophylaxis. Headache 30(7):411–417

    Article  CAS  PubMed  Google Scholar 

  • Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398(6726):436–441

    Article  CAS  PubMed  Google Scholar 

  • Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR et al (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288(5464):306–313

    Article  CAS  PubMed  Google Scholar 

  • Catterall WA, Leal K, Nanou E (2013) Calcium channels and short-term synaptic plasticity. J Biol Chem 288(15):10742–10749

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ceppa E, Cattaruzza F, Lyo V, Amadesi S, Pelayo JC, Poole DP et al (2010) Transient receptor potential ion channels V4 and A1 contribute to pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol 299(3):G556–G571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chard PS, Bleakman D, Savidge JR, Miller RJ (1995) Capsaicin-induced neurotoxicity in cultured dorsal root ganglion neurons: involvement of calcium-activated proteases. Neuroscience 65(4):1099–1108

    Article  CAS  PubMed  Google Scholar 

  • Chen M, Gu JG (2005) A P2X receptor-mediated nociceptive afferent pathway to lamina I of the spinal cord. Mol Pain 1:4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chen CC, England S, Akopian AN, Wood JN (1998) A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A 95(17):10240–10245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Alessandri-Haber N, Levine JD (2007) Marked attenuation of inflammatory mediator-induced C-fiber sensitization for mechanical and hypotonic stimuli in TRPV4−/− mice. Mol Pain 3(31):31

    PubMed  PubMed Central  Google Scholar 

  • Chopra K, Tiwari V (2012) Alcoholic neuropathy: possible mechanisms and future treatment possibilities. Br J Clin Pharmacol 73(3):348–362

    Article  CAS  PubMed  Google Scholar 

  • Cockayne DA, Hamilton SG, Zhu QM, Dunn PM, Zhong Y, Novakovic S et al (2000) Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 407(6807):1011–1015

    Article  CAS  PubMed  Google Scholar 

  • Cosens DJ, Manning A (1969) Abnormal electroretinogram from a Drosophila mutant. Nature 224(5216):285–287

    Article  CAS  PubMed  Google Scholar 

  • Coste B, Mathur J, Schmidt M, Earley TJ, Ranade S, Petrus MJ et al (2010) Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science (New York, NY) 330(6000):55–60

    Article  CAS  Google Scholar 

  • Coste B, Xiao B, Santos JS, Syeda R, Grandl J, Spencer KS et al (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483(7388):176–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cox CD, Bae C, Ziegler L, Hartley S, Nikolova-Krstevski V, Rohde PR et al (2016) Removal of the mechanoprotective influence of the cytoskeleton reveals PIEZO1 is gated by bilayer tension. Nat Commun 7:10366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • da Costa DSM, Meotti FC, Andrade EL, Leal PC, Motta EM, Calixto JB (2010) The involvement of the transient receptor potential A1 (TRPA1) in the maintenance of mechanical and cold hyperalgesia in persistent inflammation. Pain 148(3):431–437

    Article  PubMed  CAS  Google Scholar 

  • Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P et al (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405(6783):183–187

    Article  CAS  PubMed  Google Scholar 

  • Dawson RJP, Benz J, Stohler P, Tetaz T, Joseph C, Huber S et al (2012) Structure of the acid-sensing ion channel 1 in complex with the gating modifier Psalmotoxin 1. Nat Commun 3:936

    Article  PubMed  CAS  Google Scholar 

  • De Logu F, Nassini R, Materazzi S, Carvalho Gonçalves M, Nosi D, Rossi Degl’Innocenti D et al (2017) Schwann cell TRPA1 mediates neuroinflammation that sustains macrophage-dependent neuropathic pain in mice. Nat Commun 8(1):1887

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Logu F, Li Puma S, Landini L, Portelli F, Innocenti A, de Araujo DSM et al (2019) Schwann cells expressing nociceptive channel TRPA1 orchestrate ethanol-evoked neuropathic pain in mice. J Clin Invest 5:128022

    Google Scholar 

  • Deval E, Lingueglia E (2015) Acid-sensing ion channels and nociception in the peripheral and central nervous systems. Neuropharmacology 94:49–57

    Article  CAS  PubMed  Google Scholar 

  • Dietrich CJ, Morad M (2010) Synaptic acidification enhances GABAA signaling. J Neurosci 30(47):16044–16052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Diochot S, Salinas M, Baron A, Escoubas P, Lazdunski M (2007) Peptides inhibitors of acid-sensing ion channels. Toxicon 49(2):271–284

    Article  CAS  PubMed  Google Scholar 

  • Dorn G, Patel S, Wotherspoon G, Hemmings-Mieszczak M, Barclay J, Natt FJC et al (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Res 32(5):e49

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Drew LJ, Rohrer DK, Price MP, Blaver KE, Cockayne DA, Cesare P, Wood JN (2004) Acid-sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones. J Physiol 556(3):691–710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Duan B, Wu L-J, Yu Y-Q, Ding Y, Jing L, Xu L et al (2007) Upregulation of acid-sensing ion channel ASIC1a in spinal dorsal horn neurons contributes to inflammatory pain hypersensitivity. J Neurosci 27(41):11139–11148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dunn PM, Zhong Y, Burnstock G (2001) P2X receptors in peripheral neurons. Prog Neurobiol 65(2):107–134

    Article  CAS  PubMed  Google Scholar 

  • Eid SR, Crown ED, Moore EL, Liang HA, Choong KC, Dima S et al (2008) HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain 4:48

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP et al (2010) Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci U S A 107(44):19084–19089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Field MJ, Oles RJ, Lewis AS, McCleary S, Hughes J, Singh L (1997) Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. Br J Pharmacol 121(8):1513–1522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Field MJ, Cox PJ, Stott E, Melrose H, Offord J, Su TZ et al (2006) Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A 103(46):17537–17542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fredholm BB, Abbracchio MP, Burnstock G, Daly JW, Harden TK, Jacobson KA et al (1994) Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 46(2):143–156

    CAS  PubMed  Google Scholar 

  • Fu X, Yang J, Wu X, Lin Q, Zeng Y, Xia Q et al (2019) Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the she ethnic population in China. Clin Invest Med 42(1):E21–E30

    Article  PubMed  Google Scholar 

  • Gaudet AD, Popovich PG, Ramer MS (2011) Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury. J Neuroinflammation 8(110):110

    Article  PubMed  PubMed Central  Google Scholar 

  • Gavva NR (2008) Body-temperature maintenance as the predominant function of the vanilloid receptor TRPV1. Trends Pharmacol Sci 29(11):550–557

    Article  CAS  PubMed  Google Scholar 

  • Ge J, Li W, Zhao Q, Li N, Chen M, Zhi P et al (2015) Architecture of the mammalian mechanosensitive Piezo1 channel. Nature 527(7576):64–69

    Article  CAS  PubMed  Google Scholar 

  • Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN (1996) The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 271(10):5768–5776

    Article  CAS  PubMed  Google Scholar 

  • Gonzales EB, Kawate T, Gouaux E (2009) Pore architecture and ion sites in acid-sensing ion channels and P2X receptors. Nature 460(7255):599–604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gormley P, Anttila V, Winsvold BS, Palta P, Esko T, Pers TH et al (2016) Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine. Nat Genet 48(8):856–866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gross RA, Macdonald RL (1987) Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture. Proc Natl Acad Sci U S A 84(15):5469–5473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grubisha O, Mogg AJ, Sorge JL, Ball LJ, Sanger H, Ruble CL et al (2014) Pharmacological profiling of the TRPV3 channel in recombinant and native assays. Br J Pharmacol 171(10):2631–2644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Grunder S, Geissler HS, Bassler EL, Ruppersberg JP (2000) A new member of acid-sensing ion channels from pituitary gland. Neuroreport 11(8):1607–1611

    Article  CAS  PubMed  Google Scholar 

  • Hamilton NB, Kolodziejczyk K, Kougioumtzidou E, Attwell D (2016) Proton-gated Ca(2+)-permeable TRP channels damage myelin in conditions mimicking ischaemia. Nature 529(7587):523–527

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haraguchi K, Kawamoto A, Isami K, Maeda S, Kusano A, Asakura K et al (2012) TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. J Neurosci 32(11):3931–3941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hattori T, Chen J, Harding AMS, Price MP, Lu Y, Abboud FM, Benson CJ (2009) ASIC2a and ASIC3 heteromultimerize to form pH-sensitive channels in mouse cardiac dorsal root ganglia neurons. Circ Res 105(3):279–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Heiss JD, Iadarola M (2015) Intrathecal resiniferatoxin for intractable cancer pain. J Neurosurg 123:A515-A

    Google Scholar 

  • Hesselager M, Timmermann DB, Ahring PK (2004) pH dependency and desensitization kinetics of heterologously expressed combinations of acid-sensing ion channel subunits. J Biol Chem 279(12):11006–11015

    Article  CAS  PubMed  Google Scholar 

  • Hinman A, Chuang HH, Bautista DM, Julius D (2006) TRP channel activation by reversible covalent modification. Proc Natl Acad Sci U S A 103(51):19564–19568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirning LD, Fox AP, McCleskey EW, Olivera BM, Thayer SA, Miller RJ, Tsien RW (1988) Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons. Science 239(4835):57–61

    Article  CAS  PubMed  Google Scholar 

  • Holzer P (2009) Acid-sensitive ion channels and receptors. Handb Exp Pharmacol 194:283–332

    Article  CAS  Google Scholar 

  • Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, Wyatt JR et al (2002a) Analgesic profile of intrathecal P2X(3) antisense oligonucleotide treatment in chronic inflammatory and neuropathic pain states in rats. Pain 99(1–2):11–19

    Article  CAS  PubMed  Google Scholar 

  • Honore P, Mikusa J, Bianchi B, McDonald H, Cartmell J, Faltynek C, Jarvis MF (2002b) TNP-ATP, a potent P2X3 receptor antagonist, blocks acetic acid-induced abdominal constriction in mice: comparison with reference analgesics. Pain 96(1–2):99–105

    Article  CAS  PubMed  Google Scholar 

  • Huynh KW, Cohen MR, Jiang J, Samanta A, Lodowski DT, Zhou ZH, Moiseenkova-Bell VY (2016) Structure of the full-length TRPV2 channel by cryo-EM. Nat Commun 7:11130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ikeuchi M, Kolker SJ, Sluka KA (2009) Acid-sensing ion channel 3 expression in mouse knee joint afferents and effects of carrageenan-induced arthritis. J Pain 10(3):336–342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Immke DC, McCleskey EW (2001) Lactate enhances the acid-sensing NA+ channel on ischemia-sensing neurons. Nat Neurosci 4(9):869–870

    Article  CAS  PubMed  Google Scholar 

  • Jasti J, Furukawa H, Gonzales EB, Gouaux E (2007) Structure of acid-sensing ion channel 1 at 1.9 Å resolution and low pH. Nature 449(7160):316–323

    Article  CAS  PubMed  Google Scholar 

  • Jin Y, Li J, Wang Y, Ye R, Feng X, Jing Z, Zhao Z (2015) Functional role of mechanosensitive ion channel Piezo1 in human periodontal ligament cells. Angle Orthod 85(1):87–94

    Article  PubMed  Google Scholar 

  • Jones NG, Slater R, Cadiou H, McNaughton P, McMahon SB (2004) Acid-induced pain and its modulation in humans. J Neurosci 24(48):10974–10979

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jun P, Ko NU, English JD, Dowd CF, Halbach VV, Higashida RT et al (2010) Endovascular treatment of medically refractory cerebral vasospasm following aneurysmal subarachnoid hemorrhage. AJNR Am J Neuroradiol 31(10):1911–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kallenborn-Gerhardt W, Schroder K, Del Turco D, Lu R, Kynast K, Kosowski J, Schmidtko A (2012) NADPH oxidase-4 maintains neuropathic pain after peripheral nerve injury. J Neurosci 32(30):10136–10145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kamei J, Takahashi Y (2006) Involvement of ionotropic purinergic receptors in the histamine-induced enhancement of the cough reflex sensitivity in Guinea pigs. Eur J Pharmacol 547(1–3):160–164

    Article  CAS  PubMed  Google Scholar 

  • Kamei J, Takahashi Y, Yoshikawa Y, Saitoh A (2005) Involvement of P2X receptor subtypes in ATP-induced enhancement of the cough reflex sensitivity. Eur J Pharmacol 528(1–3):158–161

    Article  CAS  PubMed  Google Scholar 

  • Kanju P, Chen Y, Lee W, Yeo M, Lee SH, Romac J et al (2016) Small molecule dual-inhibitors of TRPV4 and TRPA1 for attenuation of inflammation and pain. Sci Rep 6:26894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Katsura H, Obata K, Mizushima T, Yamanaka H, Kobayashi K, Dai Y et al (2006) Antisense knock down of TRPA1, but not TRPM8, alleviates cold hyperalgesia after spinal nerve ligation in rats. Exp Neurol 200(1):112–123

    Article  CAS  PubMed  Google Scholar 

  • Kawate T, Michel JC, Birdsong WT, Gouaux E (2009) Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460(7255):592–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kellenberger S, Schild L (2015) Structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol Rev 67(1):1–35

    Article  PubMed  CAS  Google Scholar 

  • Kennedy C (2005) P2X receptors: targets for novel analgesics? Neuroscientist 11(4):345–356

    Article  CAS  PubMed  Google Scholar 

  • Khairatkar-Joshi N, Tandon M, Gudi G, Keohane P, Godsafe Z, Inventors G. P. S. A. (2016) TRPA1 antagonist for the treatment of pain associated to diabetic neuropathic pain

    Google Scholar 

  • Khakh BS (2001) Molecular physiology of P2X receptors and ATP signalling at synapses. Nat Rev Neurosci 2(3):165–174

    Article  CAS  PubMed  Google Scholar 

  • Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442(7102):527–532

    Article  CAS  PubMed  Google Scholar 

  • Khakh BS, Gittermann D, Cockayne DA, Jones A (2003) ATP modulation of excitatory synapses onto interneurons. J Neurosci 23(19):7426–7437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knowlton WM, Palkar R, Lippoldt EK, McCoy DD, Baluch F, Chen J, McKemy DD (2013) A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia. J Neurosci 33(7):2837–2848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kors EE, Terwindt GM, Vermeulen FL, Fitzsimons RB, Jardine PE, Heywood P et al (2001) Delayed cerebral edema and fatal coma after minor head trauma: role of the CACNA1A calcium channel subunit gene and relationship with familial hemiplegic migraine. Ann Neurol 49(6):753–760

    Article  CAS  PubMed  Google Scholar 

  • Kremeyer B, Lopera F, Cox JJ, Momin A, Rugiero F, Marsh S et al (2010) A gain-of-function mutation in TRPA1 causes familial episodic pain syndrome. Neuron 66(5):671–680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Krishtal O (2003) The ASICs: signaling molecules? Modulators? Trends Neurosci 26(9):477–483

    Article  CAS  PubMed  Google Scholar 

  • Kunkler PE, Zhang L, Johnson PL, Oxford GS, Hurley JH (2018) Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure. Pain 159(3):540–549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kwong K, Kollarik M, Nassenstein C, Ru F, Undem BJ (2008) P2X2 receptors differentiate placodal vs. neural crest C-fiber phenotypes innervating Guinea pig lungs and esophagus. Am J Physiol Lung Cell Mol Physiol 295(5):L858–L865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee W, Leddy HA, Chen Y, Lee SH, Zelenski NA, McNulty AL et al (2014) Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A 111(47):E5114–E5122

    CAS  PubMed  PubMed Central  Google Scholar 

  • Leone M, D’Amico D, Frediani F, Moschiano F, Grazzi L, Attanasio A, Bussone G (2000) Verapamil in the prophylaxis of episodic cluster headache: a double-blind study versus placebo. Neurology 54(6):1382–1385

    Article  CAS  PubMed  Google Scholar 

  • Liao M, Cao E, Julius D, Cheng Y (2013) Structure of the TRPV1 ion channel determined by electron cryo-microscopy. Nature 504(7478):107–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lingueglia E, De Weille JR, Bassilana F, Heurteaux C, Sakaif H, Waldmann R, Lazdunskig M (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem 272(47):29778–29783

    Article  CAS  PubMed  Google Scholar 

  • Llinas RR, Sugimori M, Cherksey B (1989) Voltage-dependent calcium conductances in mammalian neurons. The P channel. Ann N Y Acad Sci 560:103–111

    Article  CAS  PubMed  Google Scholar 

  • Macpherson LJ, Xiao B, Kwan KY, Petrus MJ, Dubin AE, Hwang S, Patapoutian A (2007) An ion channel essential for sensing chemical damage. J Neurosci 27(42):11412–11415

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz SA, Lumpkin EA (2014) Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509(7502):617–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marone IM, De Logu F, Nassini R, De Carvalho Goncalves M, Benemei S, Ferreira J et al (2018) TRPA1/NOX in the soma of trigeminal ganglion neurons mediates migraine-related pain of glyceryl trinitrate in mice. Brain 141(8):2312–2328

    Article  PubMed  PubMed Central  Google Scholar 

  • Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R, Nilius B et al (2012) TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch 463(4):561–569

    Article  CAS  PubMed  Google Scholar 

  • McCarthy MJ, Le Roux MJ, Wei H, Beesley S, Kelsoe JR, Welsh DK (2016) Calcium channel genes associated with bipolar disorder modulate lithium’s amplification of circadian rhythms. Neuropharmacology 101:439–448

    Article  CAS  PubMed  Google Scholar 

  • McGaraughty S, Chu KL, Perner RJ, Didomenico S, Kort ME, Kym PR (2010) TRPA1 modulation of spontaneous and mechanically evoked firing of spinal neurons in uninjured, osteoarthritic, and inflamed rats. Mol Pain 6(14):14

    PubMed  PubMed Central  Google Scholar 

  • McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416(6876):52–58

    Article  CAS  PubMed  Google Scholar 

  • McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M et al (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci U S A 104(33):13525–13530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Michaelson DM, Angel I (1980) Determination of delta pH in cholinergic synaptic vesicles: its effect on storage and release of acetylcholine. Life Sci 27(1):39–44

    Article  CAS  PubMed  Google Scholar 

  • Mogil JS, Breese NM, Witty MF, Ritchie J, Rainville ML, Ase A et al (2005) Transgenic expression of a dominant-negative ASIC3 subunit leads to increased sensitivity to mechanical and inflammatory stimuli. J Neurosci 25(43):9893–9901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moilanen LJ, Laavola M, Kukkonen M, Korhonen R, Leppanen T, Hogestatt ED et al (2012) TRPA1 contributes to the acute inflammatory response and mediates carrageenan-induced paw edema in the mouse. Sci Rep 2(380):380

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Monshausen GB, Miller ND, Murphy AS, Gilroy S, Miesenböck G, de Angelis DA et al (2016) Thèse Identification et caractérisation d ’ un canal chlorure, AtCLCg, impliqué dans la réponse au stress salin chez Arabidopsis thaliana. Biophys J 4(9):192–195

    Google Scholar 

  • Montell C, Rubin GM (1989) Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron 2(4):1313–1323

    Article  CAS  PubMed  Google Scholar 

  • Murthy S, Loud M et al (2018) The mechanosensitive ion channel Piezo2 mediates sensitivity to mechanical pain in mice. Sci Transl Med 10:eaat9897

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Nakatsuka T, Gu JG (2001) ATP P2X receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord. J Neurosci 21(17):6522–6531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nassini R, Materazzi S, Vriens J, Prenen J, Benemei S, De Siena G et al (2012) The “headache tree” via umbellulone and TRPA1 activates the trigeminovascular system. Brain 135(Pt 2):376–390

    Article  PubMed  Google Scholar 

  • Nassini R, Materazzi S, Benemei S, Geppetti P (2014) The TRPA1 channel in inflammatory and neuropathic pain and migraine. Rev Physiol Biochem Pharmacol 167:1–43

    Article  CAS  PubMed  Google Scholar 

  • Nieto-Rostro M, Ramgoolam K, Pratt WS, Kulik A, Dolphin AC (2018) Ablation of alpha2delta-1 inhibits cell-surface trafficking of endogenous N-type calcium channels in the pain pathway in vivo. Proc Natl Acad Sci U S A 115(51):E12043–E12052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nilius B, Voets T (2013) The puzzle of TRPV4 channelopathies. EMBO Rep 14(2):152–163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nilius B, Appendino G, Owsianik G (2012) The transient receptor potential channel TRPA1: from gene to pathophysiology. Pflugers Arch 464(5):425–458

    Article  CAS  PubMed  Google Scholar 

  • Nörenberg W, Illes P (2000) Neuronal P2X receptors: localisation and functional properties. Naunyn Schmiedeberg’s Arch Pharmacol 362(4):324–339

    Article  PubMed  Google Scholar 

  • Noto C, Pappagallo M, Szallasi A (2009) NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain. Curr Opin Investig Drugs 10(7):702–710

    CAS  PubMed  Google Scholar 

  • Nowycky MC, Fox AP, Tsien RW (1985) Three types of neuronal calcium channel with different calcium agonist sensitivity. Nature 316(6027):440–443

    Article  CAS  PubMed  Google Scholar 

  • Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Farkkila M et al (2008) A high-density association screen of 155 ion transport genes for involvement with common migraine. Hum Mol Genet 17(21):3318–3331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paulsen CE, Armache JP, Gao Y, Cheng Y, Julius D (2015) Structure of the TRPA1 ion channel suggests regulatory mechanisms. Nature 520(7548):511–517

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Petersen AS, Barloese MCJ, Snoer A, Soerensen AMS, Jensen RH (2019) Verapamil and cluster headache: still a mystery. A narrative review of efficacy, mechanisms and perspectives. Headache 24(10):13603

    Google Scholar 

  • Petrus M, Peier AM, Bandell M, Hwang SW, Huynh T, Olney N et al (2007) A role of TRPA1 in mechanical hyperalgesia is revealed by pharmacological inhibition. Mol Pain 3:40

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Plummer MR, Logothetis DE, Hess P (1989) Elementary properties and pharmacological sensitivities of calcium channels in mammalian peripheral neurons. Neuron 2(5):1453–1463

    Article  CAS  PubMed  Google Scholar 

  • Prado FC, Araldi D, Vieira AS, Oliveira-Fusaro MCG, Tambeli CH, Parada CA (2013) Neuronal P2X3 receptor activation is essential to the hyperalgesia induced by prostaglandins and sympathomimetic amines released during inflammation. Neuropharmacology 67:252–258

    Article  CAS  PubMed  Google Scholar 

  • Price MP, Snydert PM, Welsh MJ (1996) Cloning and expression of a novel human brain Na+ channel. J Biol Chem 271(14):7879–7882

    Article  CAS  PubMed  Google Scholar 

  • Price MP, McIlwrath SL, Xie J, Cheng C, Qiao J, Tarr DE et al (2001) The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32(6):1071–1083

    Article  CAS  PubMed  Google Scholar 

  • Proudfoot CJ, Garry EM, Cottrell DF, Rosie R, Anderson H, Robertson DC et al (2006) Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr Biol 16(16):1591–1605

    Article  CAS  PubMed  Google Scholar 

  • Radhakrishnan R, Moore SA, Sluka KA (2003) Unilateral carrageenan injection into muscle or joint induces chronic bilateral hyperalgesia in rats. Pain 104(3):567–577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rajasekhar P, Poole DP, Liedtke W, Bunnett NW, Veldhuis NA (2015) P2Y1 receptor activation of the TRPV4 ion channel enhances purinergic signaling in satellite glial cells. J Biol Chem 290(48):29051–29062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramer MS, French GD, Bisby MA (1997) Wallerian degeneration is required for both neuropathic pain and sympathetic sprouting into the DRG. Pain 72(1–2):71–78

    Article  CAS  PubMed  Google Scholar 

  • Ranade SS, Qiu Z, Woo S-H, Hur SS, Murthy SE, Cahalan SM et al (2014a) Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc Natl Acad Sci U S A 111(28):10347–10352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ranade SS, Woo S-H, Dubin AE, Moshourab RA, Wetzel C, Petrus M et al (2014b) Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516(7529):121–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reuter U, Chiarugi A, Bolay H, Moskowitz MA (2002) Nuclear factor-kappaB as a molecular target for migraine therapy. Ann Neurol 51(4):507–516

    Article  CAS  PubMed  Google Scholar 

  • Rossi P, Fiermonte G, Pierelli F (2003) Cinnarizine in migraine prophylaxis: efficacy, tolerability and predictive factors for therapeutic responsiveness. An open-label pilot trial. Funct Neurol 18(3):155–159

    PubMed  Google Scholar 

  • Sanford M (2013) Intrathecal ziconotide: a review of its use in patients with chronic pain refractory to other systemic or intrathecal analgesics. CNS Drugs 27(11):989–1002

    Article  CAS  PubMed  Google Scholar 

  • Santicioli P, Del Bianco E, Tramontana M, Geppetti P, Maggi CA (1992) Release of calcitonin gene-related peptide like-immunoreactivity induced by electrical field stimulation from rat spinal afferents is mediated by conotoxin-sensitive calcium channels. Neurosci Lett 136(2):161–164

    Article  CAS  PubMed  Google Scholar 

  • Saotome K, Singh AK, Sobolevsky AI (2018) Determining the crystal structure of TRPV6. CRC Press/Taylor & Francis, Boca Raton, pp 275–292

    Google Scholar 

  • Sawada Y, Hosokawa H, Matsumura K, Kobayashi S (2008) Activation of transient receptor potential ankyrin 1 by hydrogen peroxide. Eur J Neurosci 27(5):1131–1142

    Article  PubMed  Google Scholar 

  • Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E (2016) The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167(3):763–773.e11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sluka KA, Gregory NS (2015) The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation. Neuropharmacology 94:58–63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Souslova V, Cesare P, Ding Y, Akopian AN, Stanfa L, Suzuki R et al (2000) Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X3 receptors. Nature 407(6807):1015–1017

    Article  CAS  PubMed  Google Scholar 

  • Stephan G, Huang L, Tang Y, Vilotti S, Fabbretti E, Yu Y et al (2018) The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel. Nat Commun 9(1):1354

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stubberud A, Flaaen NM, McCrory DC, Pedersen SA, Linde M (2019) Flunarizine as prophylaxis for episodic migraine: a systematic review with meta-analysis. Pain 160(4):762–772

    Article  CAS  PubMed  Google Scholar 

  • Suchyna TM, Tape SE, Koeppe RE, Andersen OS, Sachs F, Gottlieb PA (2004) Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers. Nature 430(6996):235–240

    Article  CAS  PubMed  Google Scholar 

  • Sutherland SP, Benson CJ, Adelman JP, McCleskey EW (2001) Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons. Proc Natl Acad Sci U S A 98(2):711–716

    Article  CAS  PubMed  Google Scholar 

  • Syeda R, Florendo MN, Cox CD, Kefauver JM, Santos JS, Martinac B, Patapoutian A (2016) Piezo1 channels are inherently mechanosensitive. Cell Rep 17(7):1739–1746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szallasi A, Blumberg PM (1989) Resiniferatoxin, a phorbol-related diterpene, acts as an ultrapotent analog of capsaicin, the irritant constituent in red pepper. Neuroscience 30(2):515–520

    Article  CAS  PubMed  Google Scholar 

  • Szczot M, Liljencrantz J, Ghitani N, Barik A, Lam R, Thompson JH et al (2018) PIEZO2 mediates injury-induced tactile pain in mice and humans. Sci Transl Med 10:eaat9892

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Szolcsanyi J, Jancso-Gabor A, Joo F (1975) Functional and fine structural characteristics of the sensory neuron blocking effect of capsaicin. Naunyn Schmiedeberg’s Arch Pharmacol 287(2):157–169

    Article  CAS  Google Scholar 

  • Takahashi N, Kuwaki T, Kiyonaka S, Numata T, Kozai D, Mizuno Y et al (2011) TRPA1 underlies a sensing mechanism for O2. Nat Chem Biol 7(10):701–711

    Article  CAS  PubMed  Google Scholar 

  • Talavera K, Nilius B, Voets T (2008) Neuronal TRP channels: thermometers, pathfinders and life-savers. Trends Neurosci 31(6):287–295

    Article  CAS  PubMed  Google Scholar 

  • Taylor-Clark TE, Ghatta S, Bettner W, Undem BJ (2009) Nitrooleic acid, an endogenous product of nitrative stress, activates nociceptive sensory nerves via the direct activation of TRPA1. Mol Pharmacol 75(4):820–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trevisan G, Benemei S, Materazzi S, De Logu F, De Siena G, Fusi C, Nassini R (2016) TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain 139:1361–1377

    Article  PubMed  Google Scholar 

  • Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B et al (2002) Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5(6):546–551

    Article  CAS  PubMed  Google Scholar 

  • Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci U S A 104:13519–13524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuda M, Koizumi S, Kita A, Shigemoto Y, Ueno S, Inoue K (2000) Mechanical allodynia caused by intraplantar injection of P2X receptor agonist in rats: involvement of heteromeric P2X2/3 receptor signaling in capsaicin-insensitive primary afferent neurons. J Neurosci 20(15):RC90

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ugawa S, Ueda T, Ishida Y, Nishigaki M, Shibata Y, Shimada S (2002) Amiloride-blockable acid-sensing ion channels are leading acid sensors expressed in human nociceptors. J Clin Investig 110(8):1185–1190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Usoskin D, Furlan A, Islam S, Abdo H, Lönnerberg P, Lou D, et al (2015) Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 18:145–153

    Article  PubMed  CAS  Google Scholar 

  • Vandewauw I, De Clercq K, Mulier M, Held K, Pinto S, Van Ranst N et al (2018) A TRP channel trio mediates acute noxious heat sensing. Nature 555(7698):662–666

    Article  CAS  PubMed  Google Scholar 

  • Voets T, Talavera K, Owsianik G, Nilius B (2005) Sensing with TRP channels. Nat Chem Biol 1(2):85–92

    Article  CAS  PubMed  Google Scholar 

  • Voilley N, de Weille J, Mamet J, Lazdunski M (2001) Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors. J Neurosci 21(20):8026–8033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • von Hehn CA, Baron R, Woolf CJ (2012) Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron 73(4):638–652

    Article  CAS  Google Scholar 

  • Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X et al (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70(3):482–494

    Article  CAS  PubMed  Google Scholar 

  • Vulchanova L, Riedl MS, Shuster SJ, Buell G, Surprenant A, North RA, Elde R (1997) Immunohistochemical study of the P2X2 and P2X3 receptor subunits in rat and monkey sensory neurons and their central terminals. Neuropharmacology 36(9):1229–1242

    Article  CAS  PubMed  Google Scholar 

  • Walder RY, Rasmussen LA, Rainier JD, Light AR, Wemmie JA, Sluka KA (2010) ASIC1 and ASIC3 play different roles in the development of hyperalgesia after inflammatory muscle injury. J Pain 11(3):210–218

    Article  CAS  PubMed  Google Scholar 

  • Waldmann R, Lazdunski M (1998) H(+)-gated cation channels: neuronal acid sensors in the NaC/DEG family of ion channels. Curr Opin Neurobiol 8(3):418–424

    Article  CAS  PubMed  Google Scholar 

  • Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M (1997) A proton-gated cation channel involved in acid-sensing. Nature 386(6621):173–177

    Article  CAS  PubMed  Google Scholar 

  • Waldmann R, Champigny G, Lingueglia E, De Weille JR, Heurteaux C, Lazdunski M (1999) H(+)-gated cation channels. Ann N Y Acad Sci 868:67–76

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Zhou H, Zhang M, Liu W, Deng T, Zhao Q et al (2019) Structure and mechanogating of the mammalian tactile channel PIEZO2. Nature 573(7773):225–229

    Article  CAS  PubMed  Google Scholar 

  • Weigand LA, Ford AP, Undem BJ (2012) A role for ATP in bronchoconstriction-induced activation of Guinea pig vagal intrapulmonary C-fibres. J Physiol 590(16):4109–4120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wemmie JA, Chen J, Askwith CC, Hruska-Hageman AM, Price MP, Nolan BC et al (2002) The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron 34(3):463–477

    Article  CAS  PubMed  Google Scholar 

  • Wemmie JA, Price MP, Welsh MJ (2006) Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci 29(10):578–586

    Article  CAS  PubMed  Google Scholar 

  • Wemmie JA, Taugher RJ, Kreple CJ (2013) Acid-sensing ion channels in pain and disease. Nat Rev Neurosci 14(7):461–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wes PD, Chevesich J, Jeromin A, Rosenberg C, Stetten G, Montell C (1995) TRPC1, a human homolog of a Drosophila store-operated channel. Proc Natl Acad Sci U S A 92(21):9652–9656

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wheeler DG, Groth RD, Ma H, Barrett CF, Owen SF, Safa P, Tsien RW (2012) Ca(V)1 and Ca(V)2 channels engage distinct modes of Ca(2+) signaling to control CREB-dependent gene expression. Cell 149(5):1112–1124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woo S-H, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z et al (2014) Piezo2 is required for Merkel-cell mechanotransduction. Nature 509(7502):622–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woo S-H, Lukacs V, de Nooij JC, Zaytseva D, Criddle CR, Francisco A et al (2015) Piezo2 is the principal mechanotransduction channel for proprioception. Nat Neurosci 18(12):1756–1762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu L-J, Duan B, Mei Y-D, Gao J, Chen J-G, Zhuo M et al (2004) Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J Biol Chem 279(42):43716–43724

    Article  CAS  PubMed  Google Scholar 

  • Yagi J, Wenk HN, Naves LA, McCleskey EW (2006) Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ Res 99(5):501–509

    Article  CAS  PubMed  Google Scholar 

  • Yu Y, Chen Z, Li W-G, Cao H, Feng E-G, Yu F et al (2010) A nonproton ligand sensor in the acid-sensing ion channel. Neuron 68(1):61–72

    Article  CAS  PubMed  Google Scholar 

  • Zamponi GW, Striessnig J, Koschak A, Dolphin AC (2015) The physiology, pathology, and pharmacology of voltage-gated calcium channels and their future therapeutic potential. Pharmacol Rev 67(4):821–870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang N, Zhang P, Zhang X, Yang Y (2012) The efficacy of resiniferatoxin in prevention of catheter related bladder discomfort in patients after TURP - a pilot, randomized, open study. Transl Androl Urol 1(1):14–18

    PubMed  PubMed Central  Google Scholar 

  • Zhang M, Wang Y, Geng J, Zhou S, Xiao B (2019) Mechanically activated piezo channels mediate touch and suppress acute mechanical pain response in mice. Cell Rep 26(6):1419–1431.e4

    Article  CAS  PubMed  Google Scholar 

  • Zhu X, Chu PB, Peyton M, Birnbaumer L (1995) Molecular cloning of a widely expressed human homologue for the Drosophila trp gene. FEBS Lett 373(3):193–198

    Article  CAS  PubMed  Google Scholar 

  • Zubcevic L, Herzik MA Jr, Chung BC, Liu Z, Lander GC, Lee SY (2016) Cryo-electron microscopy structure of the TRPV2 ion channel. Nat Struct Mol Biol 23(2):180–186

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy

    Francesco De Logu & Pierangelo Geppetti

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  1. Francesco De Logu
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  2. Pierangelo Geppetti
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  1. Center for Substance Abuse Research, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA

    James E. Barrett

  2. Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK

    Clive P. Page

  3. Department of Pharmacology, Johannes Gutenberg University, Mainz, Rheinland-Pfalz, Germany

    Martin C. Michel

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De Logu, F., Geppetti, P. (2019). Ion Channel Pharmacology for Pain Modulation. In: Barrett, J., Page, C., Michel, M. (eds) Concepts and Principles of Pharmacology. Handbook of Experimental Pharmacology, vol 260. Springer, Cham. https://doi.org/10.1007/164_2019_336

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