Capsaicin-sensitive C- and A-fibre nociceptors control long-term potentiation-like pain amplification in humans

Brain

Volumn 138, Issue 9, 2015, Pages 2505-2520

  Henrich, Florian ^a   Magerl, Walter ^a   Klein, Thomas ^a,b   Greffrath, Wolfgang ^a   Treede, Rolf Detlef ^a  

^a UNIVERSITY OF HEIDELBERG   (Germany)

^b Mundipharma Research   (Germany)

Author keywords

central sensitisation; dynamic mechanical allodynia; hyperalgesia; peptidergic nociceptors; transient receptor potential channels (TRPV1)

Indexed keywords

CAPSAICIN; TRANSIENT RECEPTOR POTENTIAL CHANNEL 1; AGENTS ACTING ON THE PERIPHERAL NERVOUS AND NEUROMUSCULAR SYSTEMS; TRPV1 PROTEIN, HUMAN; VANILLOID RECEPTOR;

A FIBER NOCICEPTOR; ADULT; ALLODYNIA; ARTICLE; C FIBER NOCICEPTOR; CONTROLLED STUDY; DESENSITIZATION; ELECTROSTIMULATION; HEAT PAIN THRESHOLD; HUMAN; HYPERALGESIA; LONG TERM POTENTIATION; MALE; MECHANICAL STIMULUS TEST; NERVE BLOCK; NERVE COMPRESSION; NERVE FIBER; NOCICEPTION; NORMAL HUMAN; PAIN AMPLIFICATION; PAIN RECEPTOR; PRIORITY JOURNAL; SPATIAL SUMMATION; TOUCH; YOUNG ADULT; BIOPHYSICS; CHEMICALLY INDUCED; DRUG EFFECTS; INNERVATION; METABOLISM; NERVE CONDUCTION; PAIN; PAIN THRESHOLD; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; SKIN; STIMULATION;

ADULT; BIOPHYSICS; CAPSAICIN; ELECTRIC STIMULATION; HEALTHY VOLUNTEERS; HUMANS; HYPERALGESIA; LONG-TERM POTENTIATION; MALE; NERVE FIBERS; NEURAL CONDUCTION; NOCICEPTORS; PAIN; PAIN THRESHOLD; PHYSICAL STIMULATION; SENSORY SYSTEM AGENTS; SKIN; TRPV CATION CHANNELS; YOUNG ADULT;

EID: 84940746371     PISSN: 00068950     EISSN: 14602156     Source Type: Journal    
DOI: 10.1093/brain/awv108     Document Type: Article

References (134)

1. Adriaensen H, Gybels J, Handwerker HO, Van Hees J. Response properties of thin myelinated (A-delta) fibers in human skin nerves. J Neurophysiol 1983; 49: 111-22.
2. Akbar A, Yiangou Y, Facer P, Brydon WG, Walters JR, Anand P, et al. Expression of the TRPV1 receptor differs in quiescent inflammatory bowel disease with or without abdominal pain. Gut 2010; 59: 767-74.
3. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011; 107: 490-502.
4. Anand U, Otto WR, Casula MA, Day NC, Davis JB, Bountra C, et al. The effect of neurotrophic factors on morphology, TRPV1 expression and capsaicin responses of cultured human DRG sensory neurons. Neurosci Lett 2006; 399: 51-6.
5. Andrew D, Greenspan JD. Peripheral coding of tonic mechanical cutaneous pain: comparison of nociceptor activity in rat and human psychophysics. J Neurophysiol 1999; 82: 2641-8.
6. Bachy I, Franck MC, Li L, Abdo H, Pattyn A, Ernfors P. The transcription factor Cux2 marks development of an A-delta sublineage of TrkA sensory neurons. Dev Biol 2011; 360: 77-86.
7. Backonja M, Wallace MS, Blonsky ER, Cutler BJ, Malan P Jr, Rauck R, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol 2008; 7: 1106-12.
8. Banik RK, Brennan TJ. Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain 2009; 141: 41-51.
9. Barabas ME, Stucky CL. TRPV1, but not TRPA1, in primary sensory neurons contributes to cutaneous incision-mediated hypersensitivity. Mol Pain 2013; 9: 9.
10. Baumann TK, Simone DA, Shain CN, LaMotte RH. Neurogenic hyperalgesia: the search for the primary cutaneous afferent fibers that contribute to capsaicin-induced pain and hyperalgesia. J Neurophysiol 1991; 66: 212-27.
11. Binder A, May D, Baron R, Maier C, Tölle TR, Treede RD, et al. Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients. PLoS One 2011; 6: e17387.
12. Brenneis C, Kistner K, Puopolo M, Segal D, Roberson D, Sisignano M, et al. Phenotyping the function of TRPV1-expressing sensory neurons by targeted axonal silencing. J Neurosci 2013; 33: 315-26.
13. Bromm B, Jahnke MT, Treede RD. Responses of human cutaneous afferents to CO2 laser stimuli causing pain. Exp Brain Res 1984; 55: 158-66.
14. Bromm B, Neitzel H, Tecklenburg A, Treede RD. Evoked cerebral potential correlates of C-fibre activity in man. Neurosci Lett 1983; 43: 109-14.
15. Campero M, Bostock H. Unmyelinated afferents in human skin and their responsiveness to low temperature. Neurosci Lett 2010; 470: 188-92.
16. Campero M, Serra J, Ochoa JL. Peripheral projections of sensory fascicles in the human superficial radial nerve. Brain 2005; 128: 892-5.
17. Cavanaugh DJ, Chesler AT, Braz JM, Shah NM, Julius D, Basbaum AI. Restriction of transient receptor potential vanilloid-1 to the peptidergic subset of primary afferent neurons follows its developmental downregulation in nonpeptidergic neurons. J Neurosci 2011; 31: 10119-27.
18. Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, et al. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci USA 2009; 106: 9075-80.
19. Chan CL, Facer P, Davis JB, Smith GD, Egerton J, Bountra C, et al. Sensory fibres expressing capsaicin receptor TRPV1 in patients with rectal hypersensitivity and faecal urgency. Lancet 2003; 361: 385-91.
20. Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 2006; 129: 1-15.
21. Cruccu G, Pennisi E, Truini A, Iannetti GD, Romaniello A, Le Pera D, et al. Unmyelinated trigeminal pathways as assessed by laser stimuli in humans. Brain 2003; 126: 2246-56.
22. Derry S, Sven-Rice A, Cole P, Tan T, Moore RA. Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2013; 2: CD007393.
23. Dirajlal S, Pauers LE, Stucky CL. Differential response properties of IB(4)-positive and-negative unmyelinated sensory neurons to protons and capsaicin. J Neurophysiol 2003; 89: 513-24.
24. Facer P, Casula MA, Smith GD, Benham CD, Chessell IP, Bountra C, et al. Differential expression of the capsaicin receptor TRPV1 and related novel receptors TRPV3, TRPV4 and TRPM8 in normal human tissues and changes in traumatic and diabetic neuropathy. BMC Neurol 2007; 7: 11.
25. Finnerup NB, Jensen TS. Mechanisms of disease: mechanism-based classification of neuropathic pain-a critical analysis. Nat Clin Pract Neurol 2006; 2: 107-15.
26. Fuchs PN, Pappagallo M, Meyer RA. Topical EMLA pre-treatment fails to decrease the pain induced by 1% topical capsaicin. Pain 1999; 80: 637-42.
27. Garell PC, McGillis SL, Greenspan JD. Mechanical response properties of nociceptors innervating feline hairy skin. J Neurophysiol 1996; 75: 1177-89.
28. Gopinath P, Wan E, Holdcroft A, Facer P, Davis JB, Smith GD, et al. Increased capsaicin receptor TRPV1 in skin nerve fibres and related vanilloid receptors TRPV3 and TRPV4 in keratinocytes in human breast pain. BMC Women's Health 2005; 5: 2.
29. Greenspan JD, Craft RM, LeResche L, Arendt-Nielsen L, Berkley KJ, Fillingim RB, et al. Studying sex and gender differences in pain and analgesia: A consensus report. Pain 2007; 132 (Suppl 1): S26-45.
30. Guo A, Vulchanova L, Wang J, Li X, Elde R. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 1999; 11: 946-58.
31. Hansen N, Klein T, Magerl W, Treede RD. Psychophysical evidence for long-term potentiation of C-fiber and Adelta-fiber pathways in humans by analysis of pain descriptors. J Neurophysiol 2007; 97: 2559-63.
32. Heinke B, Balzer E, Sandkuhler J. Pre-and postsynaptic contributions of voltage-dependent Ca2+ channels to nociceptive transmission in rat spinal lamina I neurons. Eur J Neurosci 2004; 19: 103-11.
33. Heppelmann B, Heuss C, Schmidt RF. Fiber size distribution of myelinated and unmyelinated axons in the medial and posterior articular nerves of the cat's knee joint. Somatosens Res 1988; 5: 273-81.
34. Hines AE, Birn H, Teglbjaerg PS, Sinkjaer T. Fiber type composition of articular branches of the tibial nerve at the knee joint in man. Anat Rec 1996; 246: 573-8.
35. Hjerling-Leffler J, Alqatari M, Ernfors P, Koltzenburg M. Emergence of functional sensory subtypes as defined by transient receptor potential channel expression. J Neurosci 2007; 27: 2435-43.
36. Höper J, Helfert S, Heskamp ML, Maihöfner CG, Baron R. High concentration capsaicin for treatment of peripheral neuropathic pain: effect on somatosensory symptoms and identification of treatment responders. Curr Med Res Opin 2014; 30: 565-74.
37. Hsieh YL, Lin CL, Chiang H, Fu YS, Lue JH, Hsieh ST. Role of peptidergic nerve terminals in the skin: reversal of thermal sensation by calcitonin gene-related peptide in TRPV1-depleted neuropathy. PloS One 2012; 7: e50805.
38. Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J. VR1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci 2001; 13: 2105-14.
39. Ikeda H, Heinke B, Ruscheweyh R, Sandkühler J. Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 2003; 299: 1237-40.
40. Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006; 312: 1659-62.
41. Inui K, Kakigi R. Pain perception in humans: use of intraepidermal electrical stimulation. J Neurol Neurosurg Psychiatry 2012; 83: 551-6.
42. Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 2003; 26: 696-705.
43. Kennedy WR, Vanhove GF, Lu SP, Tobias J, Bley KR, Walk D, et al. A randomized, controlled, open-label study of the long-term effects of NGX-4010, a high-concentration capsaicin patch, on epidermal nerve fiber density and sensory function in healthy volunteers. J Pain 2010; 11: 579-87.
44. Khasabov SG, Rogers SD, Ghilardi JR, Peters CM, Mantyh PW, Simone DA. Spinal neurons that possess the substance P receptor are required for the development of central sensitization. J Neurosci 2002; 22: 9086-98.
45. Kim HY, Park CK, Cho IH, Jung SJ, Kim JS, Oh SB. Differential Changes in TRPV1 expression after trigeminal sensory nerve injury. J Pain 2008; 9: 280-8.
46. Klein T, Magerl W, Hopf HC, Sandkuhler J, Treede RD. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 2004; 24: 964-71.
47. Klein T, Magerl W, Rolke R, Treede RD. Human surrogate models of neuropathic pain. Pain 2005; 115: 227-33.
48. Klein T, Magerl W, Treede RD. Perceptual correlate of nociceptive long-term potentiation (LTP) in humans shares the time course of early-LTP. J Neurophysiol 2006; 96: 3551-5.
49. Klein T, Stahn S, Magerl W, Treede R-D. The role of heterosynaptic facilitation in long-term potentiation (LTP) of human pain sensation. Pain 2008; 139: 507-19.
50. Kress M, Koltzenburg M, Reeh PW, Handwerker HO. Responsiveness and functional attributes of electrically localized terminals of cutaneous C-fibers in vivo and in vitro. J Neurophysiol 1992; 68: 581-95.
51. LaMotte RH, Shain CN, Simone DA, Tsai EF. Neurogenic hyperalgesia: Psychophysical studies of underlying mechanisms. J Neurophysiol 1991; 66: 190-211.
52. LaMotte RH, Thalhammer JG. Response properties of highthreshold cutaneous cold receptors in the primate. Brain Res 1982; 244: 279-87.
53. Lang S, Klein T, Magerl W, Treede RD. Modality-specific sensory changes in humans after the induction of long-term potentiation (LTP) in cutaneous nociceptive pathways. Pain 2007; 128: 254-63.
54. Lawson JJ, McIlwrath SL, Woodbury CJ, Davis BM, Koerber HR. TRPV1 unlike TRPV2 is restricted to a subset of mechanically insensitive cutaneous nociceptors responding to heat. J Pain 2008; 9: 298-308.
55. Lawson SN, Crepps B, Perl ER. Calcitonin gene-related peptide immunoreactivity and afferent receptive properties of dorsal root ganglion neurones in guinea-pigs. J Physiol 2002; 540: 989-1002.
56. Lawson SN, Crepps BA, Perl ER. Relationship of substance P to afferent characteristics of dorsal root ganglion neurones in guineapig. J Physiol 1997; 505: 177-91.
57. Lozier AP, Kendig JJ. Long-term potentiation in an isolated peripheral nerve-spinal cord preparation. J Neurophysiol 1995; 74: 1001-9.
58. Ma QP. Expression of capsaicin receptor (VR1) by myelinated primary afferent neurons in rats. Neurosci Lett 2002; 319: 87-90.
59. Magerl W, Ali Z, Ellrich J, Meyer RA, Treede RD. C-and A deltafiber components of heat-evoked cerebral potentials in healthy human subjects. Pain 1999; 82: 127-37.
60. Magerl W, Fuchs PN, Meyer RA, Treede RD. Roles of capsaicininsensitive nociceptors in cutaneous pain and secondary hyperalgesia. Brain 2001; 124: 1754-64.
61. Magerl W, Szolcsányi J, Westerman RA, Handwerker HO. Laser Doppler measurements of skin vasodilation elicited by percutaneous electrical stimulation of nociceptors in humans. Neurosci Lett 1987; 82: 349-54.
62. Magerl W, Wilk SH, Treede RD. Secondary hyperalgesia and perceptual wind-up following intradermal injection of capsaicin in humans. Pain 1998; 74: 257-68.
63. Maier C, Baron R, Tölle TR, Binder A, Birbaumer N, Birklein F, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 2010; 150: 439-50.
64. Malmberg AB, Mizisin AP, Calcutt NA, von Stein T, Robbins WR, Bley KR. Reduced heat sensitivity and epidermal nerve fiber immunostaining following single applications of a high-concentration capsaicin patch. Pain 2004; 111: 360-7.
65. Maihöfner CGL, Heskamp ML. Treatment of peripheral neuropathic pain by topical capsaicin: Impact of pre-existing pain in the QUEPPstudy. Eur J Pain 2014; 18: 671-9.
66. Martin VT. Ovarian hormones and pain response: A review of clinical and basic science studies. Gend Med 2009; 6 (Suppl 2): 168-92.
67. McCoy ES, Taylor-Blake B, Zylka MJ. CGRPalpha-expressing sensory neurons respond to stimuli that evoke sensations of pain and itch. PloS One 2012; 7: e36355.
68. Messlinger K, Pawlak M, Steinbach H, Trost B, Schmidt RF. A new combination of methods for the localization, identification, and three-dimensional reconstruction of the sensory endings of articular afferents characterized by electrophysiology. Cell Tissue Res 1995; 281: 283-94.
69. Meyer RA, Davis KD, Cohen RH, Treede RD, Campbell JN. Mechanically insensitive afferents (MIAs) in cutaneous nerves of monkey. Brain Res 1991; 561: 252-61.
70. Mitchell K, Lebovitz EE, Keller JM, Mannes AJ, Nemenov MI, Iadarola MJ. Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion. Pain. 2014; 155: 733-45.
71. Mouraux A, Iannetti GD, Plaghki L. Low intensity intra-epidermal electrical stimulation can activate Adelta-nociceptors selectively. Pain 2010; 150: 199-207.
72. Naka A, Gruber-Schoffnegger D, Sandkuhler J. Non-Hebbian plasticity at C-fiber synapses in rat spinal cord lamina I neurons. Pain 2013; 154: 1333-42.
73. Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, et al. Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 1999; 286: 1558-61.
74. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: Parallel loss of epidermal nerve fibers and pain sensation. Pain 1999; 81: 135-45.
75. Ochoa J, Mair WG. The normal sural nerve in man. I. Ultrastructure and numbers of fibres and cells. Acta Neuropathol 1969; 13: 197-216.
76. Patapoutian A, Tate S, Woolf CJ. Transient receptor potential channels: targeting pain at the source. Nat Rev Drug Discov 2009; 8: 55-68.
77. Peng YB, Ringkamp M, Campbell JN, Meyer RA. Electrophysiological assessment of the cutaneous arborization of A delta-fiber nociceptors. J Neurophysiol 1999; 82: 1164-77.
78. Pertovaara A. A neuronal correlate of secondary hyperalgesia in the rat spinal dorsal horn is submodality selective and facilitated by supraspinal influence. Exp Neurol 1998; 149: 193-202.
79. Pfau DB, Klein T, Putzer D, Pogatzki-Zahn EM, Treede RD, Magerl W. Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity. Pain 2011; 152: 1532-9.
80. Pogatzki-Zahn EM, Shimizu I, Caterina M, Raja SN. Heat hyperalgesia after incision requires TRPV1 and is distinct from pure inflammatory pain. Pain 2005; 115: 296-307.
81. Qu L, Fan N, Ma C, Wang T, Han L, Fu K, et al. Enhanced excitability of MRGPRA3-and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain 2014; 137: 1039-50.
82. Rage M, Van Acker N, Facer P, Shenoy R, Knaapen MW, Timmers M, et al. The time course of CO2 laser-evoked responses and of skin nerve fibre markers after topical capsaicin in human volunteers. Clin Neurophysiol 2010; 121: 1256-66.
83. Rahn EJ, Guzman-Karlsson MC, David Sweatt J. Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory. Neurobiol Learn Mem 2013; 105: 133-50.
84. Randic M, Jiang MC, Cerne R. Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 1993; 13: 5228-41.
85. Raymond SA, Thalhammer JG, Popitz-Bergez F, Strichartz GR. Changes in axonal impulse conduction correlate with sensory modality in primary afferent fibers in the rat. Brain Res 1990; 526: 318-21.
86. Ren K, Dubner R. Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: role of BDNF-TrkB signaling and NMDA receptors. Mol Neurobiol 2007; 35: 224-35.
87. Ringkamp M, Peng YB, Wu G, Hartke TV, Campbell JN, Meyer RA. Capsaicin responses in heat-sensitive and heat-insensitive a-fiber nociceptors. J Neurosci 2001; 21: 4460-8.
88. Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkuhler J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain. 2011; 7: 20.
89. Rygh LJ, Suzuki R, Rahman W, Wong Y, Vonsy JL, Sandhu H, et al. Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Eur J Neurosci 2006; 24: 761-72.
90. Rygh LJ, Svendsen F, Fiska A, Haugan F, Hole K, Tjølsen A. Longterm potentiation in spinal nociceptive systems-how acute pain may become chronic. Psychoneuroendocrinology 2005; 30: 959-64.
91. Sandkühler J. Understanding LTP in pain pathways. Mol Pain 2007; 3: 9.
92. Sandkühler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 2009; 89: 707-58.
93. Schliessbach J, Siegenthaler A, Streitberger K, Eichenberger U, Nuesch E, Juni P, et al. The prevalence of widespread central hypersensitivity in chronic pain patients. Eur J Pain 2013; 17: 1502-10.
94. Schmalbruch H. Fiber composition of the rat sciatic nerve. Anat Rec 1986; 215: 71-81.
95. Schmelz M, Schmid R, Handwerker HO, Torebjörk HE. Encoding of burning pain from capsaicin-treated human skin in two categories of unmyelinated nerve fibres. Brain 2000; 123: 560-71.
96. Serra J, Bostock H, Sola R, Aleu J, Garcia E, Cokic B, et al. Microneurographic identification of spontaneous activity in C-nociceptors in neuropathic pain states in humans and rats. Pain 2012; 153: 42-55.
97. Shyu B-C, Vogt B. Short-term synaptic plasticity in the nociceptive thalamic-anterior cingulate pathway. Mol Pain 2009; 5: 51.
98. Simone DA, Baumann TK, LaMotte RH. Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 1989; 38: 99-107.
99. Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD. Neurogenic hyperalgesia: central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991; 66, 228-46.
100. Simpson DM, Brown S, Tobias J; NGX-4010 C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008; 70: 2305-13.
101. Sinclair DC, Stokes BAR. The production and characteristics of 'second pain'. Brain 1964; 87: 609-18.
102. Sinclair DC, Weddell G, Zander E. The relationship of cutaneous sensibility to neurohistology in the human pinna. J Anat 1952; 86: 402-11.
103. Slugg RM, Meyer RA, Campbell JN. Response of cutaneous A-and Cfiber nociceptors in the monkey to controlled-force stimuli. J Neurophysiol 2000; 83: 2179-91.
104. Snider WD, McMahon SB. Tackling pain at the source: New ideas about nociceptors. Neuron 1998; 20: 629-32.
105. Szolcsanyi J. Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 1987; 388: 9-23.
106. Tan AM, Waxman SG. Spinal cord injury, dendritic spine remodeling, and spinal memory mechanisms. Exp Neurol 2012; 235: 142-51.
107. Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, et al. The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 1998; 21: 531-43.
108. Torsney C. Inflammatory pain unmasks heterosynaptic facilitation in lamina I neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 2011; 31: 5158-68.
109. Treede RD, Meyer RA, Campbell JN. Myelinated mechanically insensitive afferents from monkey hairy skin: heat-response properties. J Neurophysiol 1998; 80: 1082-93.
110. Truini A, Garcia-Larrea L, Cruccu G. Reappraising neuropathic pain in humans-how symptoms help disclose mechanisms. Nature Rev Neurol 2013; 9: 572-82.
111. Tympanidis P, Casula MA, Yiangou Y, Terenghi G, Dowd P, Anand P. Increased vanilloid receptor VR1 innervation in vulvodynia. Eur J Pain 2004; 8: 129-33.
112. Urban MO, Gebhart GF. Supraspinal contributions to hyperalgesia. Proc Natl Acad Sci USA 1999; 96: 7687-92.
113. Vallbo AB, Olausson H, Wessberg J. Unmyelinated afferents constitute a second system coding tactile stimuli of the human hairy skin. J Neurophysiol 1999; 81: 2753-63.
114. Valtschanoff JG, Rustioni A, Guo A, Hwang SJ. Vanilloid receptor VR1 is both presynaptic and postsynaptic in the superficial laminae of the rat dorsal horn. J Comp Neurol 2001; 436: 225-35.
115. van den Broeke EN, van Heck CH, van Rijn CM, Wilder-Smith OH. Neural correlates of heterotopic facilitation induced after high frequency electrical stimulation of nociceptive pathways. Mol Pain 2011; 7: 28.
116. Vierck CJ Jr. , Kline RH, Wiley RG. Intrathecal substance p-saporin attenuates operant escape from nociceptive thermal stimuli. Neuroscience 2003; 119: 223-32.
117. Vikman KS, Kristensson K, Hill RH. Sensitization of dorsal horn neurons in a two-compartment cell culture model: wind-up and long-term potentiation-like responses. J Neurosci 2001; 21: U25-30.
118. Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ. Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 2013; 493: 669-73.
119. Wang T, Molliver DC, Jing X, Schwartz ES, Yang FC, Samad OA, et al. Phenotypic switching of nonpeptidergic cutaneous sensory neurons following peripheral nerve injury. PloS One 2011; 6: e28908.
120. Weidner C, Schmelz M, Schmidt R, Hansson B, Handwerker HO, Torebjörk HE. Functional attributes discriminating mechanoinsensitive and mechano-responsive C nociceptors in human skin. J Neurosci 1999; 19: 10184-90.
121. Wilder-Smith OH, Arendt-Nielsen L. Postoperative hyperalgesia: its clinical importance and relevance. Anesthesiology 2006; 104: 601-7.
122. Woodcock J, Witter J, Dionne RA. Stimulating the development of mechanism-based, individualized pain therapies. Nat Rev Drug Discov 2007; 6: 703-10.
123. Woolf CJ. What to call the amplification of nociceptive signals in the central nervous system that contribute to widespread pain? Pain 2014; 155: 1911-12.
124. Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, et al. Towards a mechanism-based classification of pain? Pain 1998; 77: 227-9.
125. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000; 288: 1765-9.
126. Wooten M, Weng HJ, Hartke TV, Borzan J, Klein AH, Turnquist B, et al. Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun 2014; 5: 4122.
127. Yilmaz Z, Renton T, Yiangou Y, Zakrzewska J, Chessell IP, Bountra C, et al. Burning mouth syndrome as a trigeminal small fibre neuropathy: increased heat and capsaicin receptor TRPV1 in nerve fibres correlates with pain score. J Clin Neurosci 2007; 14: 864-71.
128. Yosipovitch G, Maibach HI, Rowbotham MC. Effect of EMLA pretreatment on capsaicin-induced burning and hyperalgesia. Acta Derm Venereol. 1999; 79: 118-21.
129. Zeilhofer HU. Synaptic modulation in pain pathways. Rev Physiol Biochem Pharmacol 2005; 154: 73-100.
130. Zhang J, Cavanaugh DJ, Nemenov MI, Basbaum AI. The modalityspecific contribution of peptidergic and non-peptidergic nociceptors is manifest at the level of dorsal horn nociresponsive neurons. J Physiol 2013; 591: 1097-110.
131. Zhou LJ, Yang T, Wei X, Liu Y, Xin WJ, Chen Y, et al. Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun 2011; 25: 322-34.
132. Zhou LJ, Zhong Y, Ren WJ, Li YY, Zhang T, Liu XG. BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol 2008; 212: 507-14.
133. Ziegler EA, Magerl W, Meyer RA, Treede RD. Secondary hyperalgesia to punctate mechanical stimuli. Central sensitization to A-fibre nociceptor input. Brain 1999; 122: 2245-57.
134. Zylka MJ, Rice FL, Anderson DJ. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 2005; 45: 17-25.