REVIEW

Lifting the veil on the keratinocyte contribution to cutaneous nociception

  • Matthieu Talagas , 1,2,3,4 ,
  • Nicolas Lebonvallet 1,4 ,
  • François Berthod 2 ,
  • Laurent Misery 1,3,4
Expand
  • 1. Univ Brest, LIEN, 29200 Brest, France
  • 2. Laboratoire d’Organogenèse Expérimentale (LOEX), University of Laval, Quebec, Canada
  • 3. Department of Dermatology, Brest University Hospital, Brest, France
  • 4. Univ Brest, IBSAM (Institut Brestois de Santé Agro matière), 29200 Brest, France

Received date: 26 Jul 2019

Accepted date: 16 Dec 2019

Published date: 15 Apr 2020

Copyright

2020 The Author(s)

Abstract

Cutaneous nociception is essential to prevent individuals from sustaining injuries. According to the conventional point of view, the responses to noxious stimuli are thought to be exclusively initiated by sensory neurons, whose activity would be at most modulated by keratinocytes. However recent studies have demonstrated that epidermal keratinocytes can also act as primary nociceptive transducers as a supplement to sensory neurons. To enlighten our understanding of cutaneous nociception, this review highlights recent and relevant findings on the cellular and molecular elements that underlie the contribution of epidermal keratinocytes as nociceptive modulators and noxious sensors, both under healthy and pathological conditions.

Cite this article

Matthieu Talagas , Nicolas Lebonvallet , François Berthod , Laurent Misery . Lifting the veil on the keratinocyte contribution to cutaneous nociception[J]. Protein & Cell, 2020 , 11(4) : 239 -250 . DOI: 10.1007/s13238-019-00683-9

1
Abraira VE, Ginty DD (2013) The sensory neurons of touch. Neuron 79:618–639

DOI

2
Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24:4444–4452

DOI

3
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 28:2485–2494

DOI

4
Atoyan R, Shander D, Botchkareva NV (2009) Non-neuronal expression of transient receptor potential type A1 (TRPA1) in human skin. J Investig Dermatol 129:2312–2315

DOI

5
Bae S, Matsunaga Y, Tanaka Y, Katayama I (1999) Autocrine induction of substance P mRNA and peptide in cultured normal human keratinocytes. Biochem Biophys Res Commun 263:327–333

DOI

6
Bandell M, Story GM, Hwang SW, Viswanath V, Eid SR, Petrus MJ, Earley TJ, Patapoutian A (2004) Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41:849–857

DOI

7
Bang S, Yoo S, Yang T-J, Cho H, Hwang SW (2010) Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. J Biol Chem 285:19362–19371

DOI

8
Barr TP, Albrecht PJ, Hou Q, Mongin AA, Strichartz GR, Rice FL (2013) Air-stimulated ATP release from keratinocytes occurs through connexin hemichannels. PLoS ONE 8:e56744

DOI

9
Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

DOI

10
Baumbauer KM, DeBerry JJ, Adelman PC, Miller RH, Hachisuka J, Lee KH, Ross SE, Koerber HR, Davis BM, Albers KM (2015) Keratinocytes can modulate and directly initiate nociceptive responses. ELife. https://doi.org/10.7554/eLife.09674.001

DOI

11
Bautista DM, Jordt S-E, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282

DOI

12
Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt S-E, Julius D (2007) The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448:204–208

DOI

13
Bidaux G, Borowiec A, Gordienko D, Beck B, Shapovalov GG, Lemonnier L, Flourakis M, Vandenberghe M, Slomianny C, Dewailly E (2015) Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner. Proc Natl Acad Sci USA 112:E3345–3354

DOI

14
Boulais N, Misery L (2008) The epidermis: a sensory tissue. Eur J Dermatol EJD 18:119–127

15
Bouvier V, Roudaut Y, Osorio N, Aimonetti J-M, Ribot-Ciscar E, Penalba V, Merrot T,Lebonvallet N, Le Gall-Ianotto C, Misery L (2018) Merkel cells sense cooling with TRPM8 channels. J Investig Dermatol 138:946–956

DOI

16
del Camino D, Murphy S, Heiry M, Barrett LB, Earley TJ, Cook CA, Petrus MJ, Zhao M, D’Amours M, Deering N (2010) TRPA1 contributes to cold hypersensitivity. J Neurosci 30:15165–15174

DOI

17
Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 24:487–517

DOI

18
Caterina MJ, Pang Z (2016) TRP channels in skin biology and pathophysiology. Pharmaceuticals (Basel Switz) 9:77

DOI

19
Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389:816–824

DOI

20
Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D (1999) A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–441

DOI

21
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI, Julius D (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–313

DOI

22
Cauna N (1973) The free penicillate nerve endings of the human hairy skin. J Anat 115:277–288

23
Chuang HH, Prescott ED, Kong H, Shields S, Jordt SE, Basbaum AI, Chao MV, Julius D (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411:957–962

DOI

24
Chung M-K, Lee H, Mizuno A, Suzuki M, Caterina MJ (2004) TRPV3 and TRPV4 mediate warmth-evoked currents in primary mouse keratinocytes. J Biol Chem 279:21569–21575

DOI

25
Colburn RW, Lubin ML, Stone DJ, Wang Y, Lawrence D, D’Andrea MR, Brandt MR, Liu Y, Flores CM, Qin N (2007) Attenuated cold sensitivity in TRPM8 null mice. Neuron 54:379–386

DOI

26
Cook SP, McCleskey EW (2002) Cell damage excites nociceptors through release of cytosolic ATP. Pain 95:41–47

DOI

27
Davis KD, Pope GE (2002) Noxious cold evokes multiple sensations with distinct time courses. Pain 98:179–185

DOI

28
Davis JB, Gray J, Gunthorpe MJ, Hatcher JP, Davey PT, Overend P, Harries MH, Latcham J, Clapham C, Atkinson K (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405:183–187

DOI

29
Denda M, Fuziwara S, Inoue K, Denda S, Akamatsu H, Tomitaka A, Matsunaga K (2001) Immunoreactivity of VR1 on epidermal keratinocyte of human skin. Biochem Biophys Res Commun 285:1250–1252

DOI

30
Denda M, Tsutsumi M, Denda S (2010a) Topical application of TRPM8 agonists accelerates skin permeability barrier recovery and reduces epidermal proliferation induced by barrier insult: role of cold-sensitive TRP receptors in epidermal permeability barrier homoeostasis. Exp Dermatol 19:791–795

DOI

31
Denda M, Tsutsumi M, Goto M, Ikeyama K, Denda S(2010b) Topical application of TRPA1 agonists and brief cold exposure accelerate skin permeability barrier recovery. J Investig Dermatol 130:1942–1945

DOI

32
Dhaka A, Murray AN, Mathur J, Earley TJ, Petrus MJ, Patapoutian A (2007) TRPM8 is required for cold sensation in mice. Neuron 54:371–378

DOI

33
Di Marco E, Marchisio PC, Bondanza S, Franzi AT, Cancedda R, De Luca M (1991) Growth-regulated synthesis and secretion of biologically active nerve growth factor by human keratinocytes. J Biol Chem 266:21718–21722

34
Djouhri L, Lawson SN (2004) Abeta-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A-fiber neurons in mammals. Brain Res Rev 46:131–145

DOI

35
Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619–632

DOI

36
Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310:1495–1499

DOI

37
Fischer M, Glanz D, Urbatzka M, Brzoska T, Abels C (2009) Keratinocytes: a source of the transmitter L-glutamate in the epidermis. Exp Dermatol 18:1064–1066

DOI

38
Grando SA, Kist DA, Qi M, Dahl MV (1993) Human keratinocytes synthesize, secrete, and degrade acetylcholine. J Investig Dermatol 101:32–36

DOI

39
Greig AVH, Linge C, Terenghi G, McGrouther DA, Burnstock G (2003) Purinergic receptors are part of a functional signaling system for proliferation and differentiation of human epidermal keratinocytes. J Investig Dermatol 120:1007–1015

DOI

40
Güler AD, Lee H, Iida T, Shimizu I, Tominaga M, Caterina M (2002) Heat-evoked activation of the ion channel, TRPV4. J Neurosci 22:6408–6414

DOI

41
Haeberle H, Fujiwara M, Chuang J, Medina MM, Panditrao MV, Bechstedt S, Howard J, Lumpkin EA (2004) Molecular profiling reveals synaptic release machinery in Merkel cells. Proc Natl Acad Sci USA 101:14503–14508

DOI

42
Han SB, Kim H, Cho SH, Lee JD, Chung JH, Kim HS (2016) Transient receptor potential vanilloid-1 in epidermal keratinocytes may contribute to acute pain in herpes zoster. Acta Dermato Venereol 96:319–322

DOI

43
Hilliges M, Wang L, Johansson O (1995) Ultrastructural evidence for nerve fibers within all vital layers of the human epidermis. J Investig Dermatol 104:134–137

DOI

44
Hou Q, Barr T, Gee L, Vickers J, Wymer J, Borsani E, Rodella L, Getsios S,Burdo T, Eisenberg E (2011) Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms. Pain 152:2036–2051

DOI

45
Huang SM, Lee H, Chung M-K, Park U, Yu YY, Bradshaw HB, Coulombe PA, Walker JM, Caterina MJ (2008) Overexpressed transient receptor potential vanilloid 3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2. J Neurosci 28:13727–13737

DOI

46
Huang SM, Li X, Yu Y, Wang J, Caterina MJ (2011) TRPV3 and TRPV4 ion channels are not major contributors to mouse heat sensation. Mol Pain 7:37

DOI

47
Ikeda R, Cha M, Ling J,Jia Z, Coyle D, Gu JG (2014) Merkel cells transduce and encode tactile stimuli to drive Aβ-afferent impulses. Cell 157:664–675

DOI

48
Inoue K, Koizumi S, Fuziwara S, Denda S, Inoue K, Denda M (2002) Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 291:124–129

DOI

49
Ji R-R, Chamessian A, Zhang Y-Q (2016) Pain regulation by nonneuronal cells and inflammation. Science 354:572–577

DOI

50
Jordt S-E, Bautista DM, Chuang H-H, McKemy DD, Zygmunt PM, Högestätt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

DOI

51
Karashima Y, Talavera K, Everaerts W, Janssens A, Kwan KY, Vennekens R, Nilius B, Voets T (2009) TRPA1 acts as a cold sensor in vitro and in vivo. Proc Natl Acad Sci USA 106:1273–1278

DOI

52
Kennedy WR, Wendelschafer-Crabb G (1993) The innervation of human epidermis. J Neurol Sci 115:184–190

DOI

53
Khodorova A, Fareed MU, Gokin A, Strichartz GR, Davar G (2002) Local injection of a selective endothelin-B receptor agonist inhibits endothelin-1-induced pain-like behavior and excitation of nociceptors in a naloxone-sensitive manner. J Neurosci 22:7788–7796

DOI

54
Khodorova A, Navarro B, Jouaville LS, Murphy J-E, Rice FL, Mazurkiewicz JE, Long-Woodward D, Stoffel M, Strichartz GR, Yukhananov R (2003) Endothelin-B receptor activation triggers an endogenous analgesic cascade at sites of peripheral injury. Nat Med 9:1055–1061

DOI

55
Koizumi S, Fujishita K, Inoue K, Shigemoto-Mogami Y, Tsuda M, Inoue K (2004) Ca2+ waves in keratinocytes are transmitted to sensory neurons: the involvement of extracellular ATP and P2Y2 receptor activation. Biochem J 380:329–338

DOI

56
Kwan KY, Allchorne AJ, Vollrath MA, Christensen AP, Zhang D-S, Woolf CJ, Corey DP (2006) TRPA1 contributes to cold, mechanical, and chemical nociception but is not essential for hair-cell transduction. Neuron 50:277–289

DOI

57
Kwan KY, Glazer JM, Corey DP, Rice FL, Stucky CL (2009) TRPA1 modulates mechanotransduction in cutaneous sensory neurons. J Neurosci 29:4808–4819

DOI

58
Lee H, Iida T, Mizuno A, Suzuki M, Caterina MJ (2005) Altered thermal selection behavior in mice lacking transient receptor potential vanilloid 4. J Neurosci 25:1304–1310

DOI

59
LeMasurier M, Gillespie PG (2005) Hair-cell mechanotransduction and cochlear amplification. Neuron 48:403–415

DOI

60
Li W-W, Sabsovich I, Guo T-Z, Zhao R, Kingery WS, Clark JD (2009) The role of enhanced cutaneous IL-1beta signaling in a rat tibia fracture model of complex regional pain syndrome. Pain 144:303–313

DOI

61
Lumpkin EA, Caterina MJ (2007) Mechanisms of sensory transduction in the skin. Nature 445:858–865

DOI

62
Macpherson LJ, Geierstanger BH, Viswanath V, Bandell M, Eid SR, Hwang S, Patapoutian A (2005) The pungency of garlic: activation of TRPA1 and TRPV1 in response to allicin. Curr Biol CB 15:929–934

DOI

63
Maksimovic S, Baba Y, Lumpkin EA (2013) Neurotransmitters and synaptic components in the Merkel cell-neurite complex, a gentletouch receptor. Ann N Y Acad Sci 1279:13–21

DOI

64
Maksimovic S, Nakatani M, Baba Y, Nelson AM, Marshall KL, Wellnitz SA, Firozi P, Woo S-H, Ranade S, Patapoutian A (2014) Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509:617–621

DOI

65
McArthur JC, Stocks EA, Hauer P, Cornblath DR, Griffin JW (1998) Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 55:1513–1520

DOI

66
McKemy DD, Neuhausser WM, Julius D (2002) Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416:52–58

DOI

67
McMahon SB, Bennett DLH, Bevan S (2008) Inflammatory mediators and modulators of pain. In: McMahon SB, Koltzenburg M(eds) Wall and and Melzack’s textbook of pain. Elsevier, Philadelphia, pp 49–72

DOI

68
Moehring F, Cowie AM, Menzel AD, Weyer AD, Grzybowski M, Arzua T, Geurts AM, Palygin O, Stucky CL (2018a) Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. ELife 7:e31684

DOI

69
Moehring F, Halder P, Seal RP, Stucky CL (2018b) Uncovering the cells and circuits of touch in normal and pathological settings. Neuron 100:349–360

DOI

70
Moore C, Cevikbas F, Pasolli HA, Chen Y, Kong W, Kempkes C, Parekh P, Lee SH, Kontchou N-A, Yeh I (2013) UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc Natl Acad Sci USA 110:E3225–E3234

DOI

71
Moqrich A, Hwang SW, Earley TJ, Petrus MJ, Murray AN, Spencer KSR, Andahazy M, Story GM, Patapoutian A (2005) Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science 307:1468–1472

DOI

72
Moriyama T, Higashi T, Togashi K, Iida T, Segi E, Sugimoto Y, Tominaga T, Narumiya S, Tominaga M (2005) Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins. Mol Pain 1:3

DOI

73
Morrison KM, Miesegaes GR, Lumpkin EA, Maricich SM (2009) Mammalian Merkel cells are descended from the epidermal lineage. Dev Biol 336:76–83

DOI

74
Nahm WK, Philpot BD, Adams MM, Badiavas EV, Zhou LH, Butmarc J, Bear MF, Falanga V (2004) Significance of N-methyl-Daspartate (NMDA) receptor-mediated signaling in human keratinocytes. J Cell Physiol 200:309–317

DOI

75
Obata K, Katsura H, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A, Tominaga M, Noguchi K (2005) TRPA1 induced in sensory neurons contributes to cold hyperalgesia after inflammation and nerve injury. J Clin Investig 115:2393–2401

DOI

76
Oberwinkler J, Philipp SE (2014) TRPM3. In: Nilius B, Flockerzi V(eds) Mammalian transient receptor potential (TRP) cation channels. Springer, Berlin, pp 427–459

DOI

77
Pang Z, Sakamoto T, Tiwari V, Kim Y-S, Yang F, Dong X, Güler AD, Guan Y, Caterina MJ (2015) Selective keratinocyte stimulation is sufficient to evoke nociception in mice. Pain 156:656–665

DOI

78
Park U, Vastani N, Guan Y, Raja SN, Koltzenburg M, Caterina MJ (2011) TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception. J Neurosci 31:11425–11436

DOI

79
Pei Y, Barber LA, Murphy RC, Johnson CA, Kelley SW, Dy LC, Fertel RH, Nguyen TM, Williams DA, Travers JB (1998) Activation of the epidermal platelet-activating factor receptor results in cytokine and cyclooxygenase-2 biosynthesis. J Immunol (Baltim Md) 1950 (161):1954–1961

80
Peier AM, Moqrich A, Hergarden AC, Reeve AJ, Andersson DA, Story GM, Earley TJ, Dragoni I, McIntyre P, Bevan S (2002a) A TRP channel that senses cold stimuli and menthol. Cell 108:705–715

DOI

81
Peier AM, Reeve AJ, Andersson DA, Moqrich A, Earley TJ, Hergarden AC, Story GM, Colley S, Hogenesch JB, McIntyre P (2002b) A heat-sensitive TRP channel expressed in keratinocytes. Science 296:2046–2049

DOI

82
Pogorzala LA, Mishra SK, Hoon MA (2013) The cellular code for mammalian thermosensation. J Neurosci 33:5533–5541

DOI

83
Radtke C, Vogt PM, Devor M, Kocsis JD (2010) Keratinocytes acting on injured afferents induce extreme neuronal hyperexcitability and chronic pain. Pain 148:94–102

DOI

84
Roggenkamp D, Falkner S, Stäb F, Petersen M, Schmelz M, Neufang G (2012) Atopic keratinocytes induce increased neurite outgrowth in a coculture model of porcine dorsal root ganglia neurons and human skin cells. J Investig Dermatol 132:1892–1900

DOI

85
Sekino Y, Nakano J, Hamaue Y, Chuganji S, Sakamoto J, Yoshimura T, Origuchi T, Okita M (2014) Sensory hyperinnervation and increase in NGF, TRPV1 and P2X3 expression in the epidermis following cast immobilization in rats. Eur J Pain (Lond Engl) 18:639–648

DOI

86
Shi X, Wang L, Li X, Sahbaie P, Kingery WS, Clark JD (2011) Neuropeptides contribute to peripheral nociceptive sensitization by regulating interleukin-1β production in keratinocytes. Anesth Analg 113:175–183

DOI

87
Shi X, Wang L, Clark JD, Kingery WS (2013) Keratinocytes express cytokines and nerve growth factor in response to neuropeptide activation of the ERK1/2 and JNK MAPK transcription pathways. Regul Pept 186:92–103

DOI

88
Smith GD, Gunthorpe MJ, Kelsell RE, Hayes PD, Reilly P, Facer P, Wright JE, Jerman JC, Walhin J-P, Ooi L (2002) TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418:186–190

DOI

89
Snider WD, McMahon SB (1998) Tackling pain at the source: new ideas about nociceptors. Neuron 20:629–632

DOI

90
Sondersorg AC, Busse D, Kyereme J, Rothermel M, Neufang G, Gisselmann G, Hatt H, Conrad H (2014) Chemosensory information processing between keratinocytes and trigeminal neurons. J Biol Chem 289:17529–17540

DOI

91
Southall MD, Li T, Gharibova LS, Pei Y, Nicol GD, Travers JB (2003) Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J Pharmacol Exp Ther 304:217–222

DOI

92
Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112:819–829

DOI

93
Suzuki M, Watanabe Y, Oyama Y, Mizuno A, Kusano E, Hirao A, Ookawara S (2003) Localization of mechanosensitive channel TRPV4 in mouse skin. Neurosci Lett 353:189–192

DOI

94
Talagas M, Lebonvallet N, Misery L (2018a) Intraepidermal nerve fibres are not the exclusive tranducers of nociception. J Neurosci Methods 306:92–93

DOI

95
Talagas M, Lebonvallet N, Leschiera R, Marcorelles P, Misery L (2018b) What about physical contacts between epidermal keratinocytes and sensory neurons? Exp Dermatol 27:9–13

DOI

96
Todaka H, Taniguchi J, Satoh J, Mizuno A, Suzuki M (2004) Warm temperature-sensitive transient receptor potential vanilloid 4 (TRPV4) plays an essential role in thermal hyperalgesia. J Biol Chem 279:35133–35138

DOI

97
Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543

DOI

98
Tominaga M, Wada M, Masu M (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc Natl Acad Sci USA 98:6951–6956

DOI

99
Tsuboi R, Sato C, Oshita Y, Hama H, Sakurai T, Goto K, Ogawa H (1995) Ultraviolet B irradiation increases endothelin-1 and endothelin receptor expression in cultured human keratinocytes. FEBS Lett 371:188–190

DOI

100
Tsutsumi M, Inoue K, Denda S, Ikeyama K, Goto M, Denda M (2009) Mechanical-stimulation-evoked calcium waves in proliferating and differentiated human keratinocytes. Cell Tissue Res 338:99–106

DOI

101
Tsutsumi M, Denda S, Ikeyama K, Goto M, Denda M (2010) Exposure to low temperature induces elevation of intracellular calcium in cultured human keratinocytes. J Investig Dermatol 130:1945–1948

DOI

102
Van Keymeulen A, Mascre G, Youseff KK, Harel I, Michaux C, De Geest N, Szpalski C, Achouri Y, Bloch W, Hassan BA (2009) Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. J Cell Biol 187:91–100

DOI

103
Vandewauw I, De Clercq K, Mulier M, Held K, Pinto S, Van Ranst N, Segal A, Voet T, Vennekens R, Zimmermann K (2018) A TRP channel trio mediates acute noxious heat sensing. Nature 555:662–666

DOI

104
Vriens J, Owsianik G, Hofmann T, Philipp SE, Stab J, Chen X, Benoit M, Xue F, Janssens A, Kerselaers S (2011) TRPM3 is a nociceptor channel involved in the detection of noxious heat. Neuron 70:482–494

DOI

105
Wang L, Hilliges M, Jernberg T, Wiegleb-Edström D, Johansson O (1990) Protein gene product 9.5-immunoreactive nerve fibres and cells in human skin. Cell Tissue Res 261:25–33

DOI

106
Waxman SG, Cummins TR, Dib-Hajj SD, Black JA (2000) Voltagegated sodium channels and the molecular pathogenesis of pain: a review. J Rehabil Res Dev 37:517–528

107
Wintzen M, Yaar M, Burbach JP, Gilchrest BA (1996) Proopiomelanocortin gene product regulation in keratinocytes. J Investig Dermatol 106:673–678

DOI

108
Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410–6415

DOI

109
Woolf CJ, Ma Q (2007) Nociceptors–noxious stimulus detectors. Neuron 55:353–364

DOI

110
Xu H, Ramsey IS, Kotecha SA, Moran MM, Chong JA, Lawson D, Ge P, Lilly J, Silos-Santiago I, Xie Y (2002) TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418:181–186

DOI

111
Zanello SB, Jackson DM, Holick MF (1999) An immunocytochemical approach to the study of beta-endorphin production in human keratinocytes using confocal microscopy. Ann N Y Acad Sci 885:85–99

DOI

112
Zhao P, Barr TP, Hou Q, Dib-Hajj SD, Black JA, Albrecht PJ, Petersen K, Eisenberg E, Wymer JP, Rice FL (2008) Voltage-gated sodium channel expression in rat and human epidermal keratinocytes: evidence for a role in pain. Pain 139:90–105

DOI

113
Zimmermann K, Leffler A, Fischer MMJ, Messlinger K, Nau C, Reeh PW (2005) The TRPV1/2/3 activator 2-aminoethoxydiphenyl borate sensitizes native nociceptive neurons to heat in wildtype but not TRPV1 deficient mice. Neuroscience 135:1277–1284

DOI

114
Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25

DOI

Outlines

/