Browse > Article
http://dx.doi.org/10.5483/BMBRep.2016.49.9.108

The peripheral and central mechanisms underlying itch  

Lee, Jae Seung (Department of Brain and Cognitive Sciences, DGIST)
Han, Jasmin Sanghyun (Department of Brain and Cognitive Sciences, DGIST)
Lee, Kyeongho (Department of Brain and Cognitive Sciences, DGIST)
Bang, Juwon (Department of Brain and Cognitive Sciences, DGIST)
Lee, Hyosang (Department of Brain and Cognitive Sciences, DGIST)
Publication Information
BMB Reports / v.49, no.9, 2016 , pp. 474-487 More about this Journal
Abstract
Itch is one of the most distressing sensations that substantially impair quality of life. It is a cardinal symptom of many skin diseases and is also caused by a variety of systemic disorders. Unfortunately, currently available itch medications are ineffective in many chronic itch conditions, and they often cause undesirable side effects. To develop novel therapeutic strategies, it is essential to identify primary afferent neurons that selectively respond to itch mediators as well as the central nervous system components that process the sensation of itch and initiate behavioral responses. This review summarizes recent progress in the study of itch, focusing on itch-selective receptors, signaling molecules, neuronal pathways from the primary sensory neurons to the brain, and potential decoding mechanisms based on which itch is distinguished from pain.
Keywords
BAM8-22; Chloroquine; Cowhage; Endothelin; Histamine; Itch; MrgprA3; MrgprC11; Primary afferents; Primary sensory neurons; Protease-activated receptor; Pruritogen; Pruritus;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Ikoma A, Steinhoff M, Ständer S, Yosipovitch G and Schmelz M (2006) The neurobiology of itch. Nat Rev Neurosci 7, 535-547   DOI
2 Yosipovitch G, Greaves MW, Fleischer Jr AB and McGlone F (2004) Itch: basic mechanisms and therapy, CRC Press/Taylor & Francis, Boca Raton, Florida, USA
3 Misery L and Ständer S (2010) Pruritus, Springer, New York, USA
4 Williams HC (2000) Epidemiology of atopic dermatitis. Clin Exp Dermatol 25, 522-529   DOI
5 Sowunmi A, Fehintola F, Adedeji A et al (2000) Comparative efficacy of chloroquine plus chlorpheniramine alone and in a sequential combination with sulfadoxine–pyrimethamine, for the treatment of acute, uncomplicated, falciparum malaria in children. Ann Trop Med and Parasitol 94, 209-217   DOI
6 Silverberg JI, Nelson DB and Yosipovitch G (2016) Addressing treatment challenges in atopic dermatitis with novel topical therapies. J Dermatolog Treat 11, 1-9   DOI
7 Beauregard S and Gilchrest BA (1987) A survey of skin problems and skin care regimens in the elderly. Arch Dermatol 123, 1638-1643   DOI
8 Mnyika K and Kihamia C (1991) Chloroquine-induced pruritus: its impact on chloroquine utilization in malaria control in Dar es Salaam. J Trop Med Hyg 94, 27-31
9 LaMotte RH, Dong X and Ringkamp M (2014) Sensory neurons and circuits mediating itch. Nat Rev Neurosci 15, 19-31   DOI
10 Bautista DM, Wilson SR and Hoon MA (2014) Why we scratch an itch: the molecules, cells and circuits of itch. Nat Neurosci 17, 175-182   DOI
11 Akiyama T and Carstens E (2013) Neural processing of itch. Neuroscience 250, 697-714   DOI
12 Ständer S, Steinhoff M, Schmelz M, Weisshaar E, Metze D and Luger T (2003) Neurophysiology of pruritus: cutaneous elicitation of itch. Arch Dermatol 139, 1463-1470   DOI
13 Rowley DA and Benditt EP (1956) 5-Hydroxytryptamine and histamine as mediators of the vascular injury produced by agents which damage mast cells in rats. J Exp Med 103, 399-412   DOI
14 Simone DA, Ngeow JY, Whitehouse J, Becerra-Cabal L, Putterman GJ and Lamotte RH (1987) The magnitude and duration of itch produced by intracutaneous injections of histamine. Somatosens Res 5, 81-92   DOI
15 Shim WS and Oh U (2008) Histamine-induced itch and its relationship with pain. Mol Pain 4, 29   DOI
16 Magerl W, Westerman RA, Möhner B and Handwerker HO (1990) Properties of transdermal histamine iontophoresis: differential effects of season, gender, and body region. J Invest Dermatol 94, 347-352   DOI
17 Bell J, McQueen D and Rees J (2004) Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in BalbC mice. Br J Pharmacol 142, 374-380   DOI
18 Han SK, Mancino V and Simon MI (2006) Phospholipase Cβ 3 mediates the scratching response activated by the histamine H1 receptor on C-fiber nociceptive neurons. Neuron 52, 691-703   DOI
19 Strasser A, Wittmann HJ, Buschauer A, Schneider EH and Seifert R (2013) Species-dependent activities of G-protein-coupled receptor ligands: lessons from histamine receptor orthologs. Trends Pharmacol Sci 34, 13-32   DOI
20 Shim WS, Tak MH, Lee MH et al (2007) TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase. J Neurosci 27, 2331-2337   DOI
21 Kim BM, Lee SH, Shim WS and Oh U (2004) Histamine-induced Ca2+ influx via the PLA 2/lipoxygenase/TRPV1 pathway in rat sensory neurons. Neurosci Lett 361, 159-162   DOI
22 Imamachi N, Park GH, Lee H et al (2009) TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A 106, 11330-11335   DOI
23 Shelley WB and Arthur RP (1955) Mucunain, the active pruritogenic proteinase of cowhage. Science 122, 469-470.   DOI
24 Tuckett RP and Wei JY (1987) Response to an itch-producing substance in cat. I. Cutaneous receptor populations with myelinated axons. Brain Res 413, 87-94   DOI
25 Sikand P, Shimada SG, Green BG and LaMotte RH (2009) Similar itch and nociceptive sensations evoked by punctate cutaneous application of capsaicin, histamine and cowhage. Pain 144, 66-75   DOI
26 Johanek LM, Meyer RA, Hartke T et al (2007) Psychophysical and physiological evidence for parallel afferent pathways mediating the sensation of itch. J Neurosci 27, 7490-7497   DOI
27 Namer B, Carr R, Johanek LM, Schmelz M, Handwerker HO and Ringkamp M (2008) Separate peripheral pathways for pruritus in man. J Neurophysiol 100, 2062-2069   DOI
28 Johanek LM, Meyer RA, Friedman RM et al (2008) A role for polymodal C-fiber afferents in nonhistaminergic itch. J Neurosci 28, 7659-7669   DOI
29 Ringkamp M, Schepers RJ, Shimada SG et al (2011) A role for nociceptive, myelinated nerve fibers in itch sensation. J Neurosci 31, 14841-14849   DOI
30 Ma C, Nie H, Gu Q, Sikand P and LaMotte RH (2012) In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol 107, 357-363   DOI
31 Shelley WB and Arthur RP (1955) Studies on cowhage (Mucuna pruriens) and its pruritogenic proteinase, mucunain. AMA Arch Derm 72, 399-406   DOI
32 Reddy VB, Iuga AO, Shimada SG, LaMotte RH and Lerner EA (2008) Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J Neurosci 28, 4331-4335   DOI
33 Nystedt S, Emilsson K, Wahlestedt C and Sundelin J (1994) Molecular cloning of a potential proteinase activated receptor. Proc Natl Acad Sci U S A 91, 9208-9212   DOI
34 Han L, Ma C, Liu Q et al (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16, 174-182   DOI
35 Shimada SG, Shimada KA and Collins JG (2006) Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur J Pharmacol 530, 281-283   DOI
36 Steinhoff M, Neisius U, Ikoma A et al (2003) Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J Neurosci 23, 6176-6180
37 Liu Q and Dong X (2015) The role of the Mrgpr receptor family in itch; in Pharmacology of Itch. Handb Exp Pharmacol 226, 71-88
38 Liu Q, Tang Z, Surdenikova L et al (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139, 1353-1365   DOI
39 Lembo PM, Grazzini E, Groblewski T et al (2002) Proenkephalin A gene products activate a new family of sensory neuron–specific GPCRs. Nat Neurosci 5, 201-209   DOI
40 Sikand P, Dong X and LaMotte RH (2011) BAM8–22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci 31, 7563-7567   DOI
41 Liu Q, Sikand P, Ma C et al (2012) Mechanisms of itch evoked by β-alanine. J Neurosci 32, 14532-14537   DOI
42 Liu Q, Weng H-J, Patel KN et al (2011) The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci Signal 4, ra45
43 Reddy VB, Sun S, Azimi E, Elmariah SB, Dong X and Lerner EA (2015) Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs. Nat Commun 6, 7864   DOI
44 Zylka MJ, Dong X, Southwell AL and Anderson DJ (2003) Atypical expansion in mice of the sensory neuron-specific Mrg G protein-coupled receptor family. Proc Natl Acad Sci U S A 100, 10043-10048   DOI
45 Kuraishi Y, Nagasawa T, Hayashi K and Satoh M (1995) Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Euro J Pharmacol 275, 229-233   DOI
46 Shinohara T, Harada M, Ogi K et al (2004) Identification of a G protein-coupled receptor specifically responsive to β-alanine. J Biol Chem 279, 23559-23564   DOI
47 Dong X, Han S-k, Zylka MJ, Simon MI and Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106, 619-632   DOI
48 Wilson S and Bautista D (2013) Itching for relief. Nat Neurosci 16, 775-777   DOI
49 Story GM, Peier AM, Reeve AJ et al (2003) ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819-829   DOI
50 Ferreira S, Romitelli M and De Nucci G (1989) Endothelin-1 participation in overt and inflammatory pain. J Cardiovasc Pharmacol 13 Suppl 5, S220-222   DOI
51 Katugampola R, Church MK and Clough GF (2000) The neurogenic vasodilator response to endothelin-1: a study in human skin in vivo. Exp Physiol 85, 839-846   DOI
52 Gomes LO, Hara DB and Rae GA (2012) Endothelin-1 induces itch and pain in the mouse cheek model. Life Sci 91, 628-633   DOI
53 Andoh T, Yoshida T, Lee J-B and Kuraishi Y (2012) Cathepsin E induces itch-related response through the production of endothelin-1 in mice. Eur J Pharmacol 686, 16-21   DOI
54 Jinks SL and Carstens E (2002) Responses of superficial dorsal horn neurons to intradermal serotonin and other irritants: comparison with scratching behavior. J Neurophysiol 87, 1280-1289   DOI
55 Akiyama T, Carstens MI and Carstens E (2010) Facial injections of pruritogens and algogens excite partly overlapping populations of primary and second-order trigeminal neurons in mice. J Neurophysiol 104, 2442-2450   DOI
56 Yamaguchi T, Nagasawa T, Satoh M and Kuraishi Y (1999) Itch-associated response induced by intradermal serotonin through 5-HT 2 receptors in mice. Neurosci Res 35, 77-83   DOI
57 Thomsen JS, Petersen M, Benfeldt E, Jensen S and Serup J (2001) Scratch induction in the rat by intradermal serotonin: a model for pruritus. Acta Derm Venereol 81, 250-254   DOI
58 Nojima H and Carstens E (2003) 5-Hydroxytryptamine (5-HT) 2 receptor involvement in acute 5-HT-evoked scratching but not in allergic pruritus induced by dinitrofluorobenzene in rats. J Pharmacol Exp Ther 306, 245-252   DOI
59 Carstens E (1997) Responses of rat spinal dorsal horn neurons to intracutaneous microinjection of histamine, capsaicin, and other irritants. J Neurophysiol 77, 2499-2514   DOI
60 Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA and Giesler GJ, Jr. (2007) The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J Neurosci 27, 10007-10014   DOI
61 Simone DA, Zhang X, Li J et al (2004) Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J Neurophysiol 91, 213-222   DOI
62 Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjörk H and Handwerker HO (2003) Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J Neurophysiol 89, 2441-2448   DOI
63 Nicolson T, Bevan S and Richards C (2002) Characterisation of the calcium responses to histamine in capsaicinsensitive and capsaicin-insensitive sensory neurones. Neuroscience 110, 329-338   DOI
64 Schmelz M, Schmidt R, Bickel A, Handwerker HO and Torebjork HE (1997) Specific C-receptors for itch in human skin. J Neurosci 17, 8003-8008
65 LaMotte RH, Shimada SG, Green BG and Zelterman D (2009) Pruritic and nociceptive sensations and dysesthesias from a spicule of cowhage. J Neurophysiol 101, 1430-1443   DOI
66 Klein A, Carstens MI and Carstens E (2011) Facial injections of pruritogens or algogens elicit distinct behavior responses in rats and excite overlapping populations of primary sensory and trigeminal subnucleus caudalis neurons. J Neurophysiol 106, 1078-1088   DOI
67 Amadesi S, Nie J, Vergnolle N et al (2004) Protease-activated receptor 2 sensitizes the capsaicin receptor transient receptor potential vanilloid receptor 1 to induce hyperalgesia. J Neurosci 24, 4300-4312   DOI
68 Spike R, Puskar Z, Andrew D and Todd A (2003) A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur J Neurosci 18, 2433-2448   DOI
69 Fleming MS, Ramos D, Han SB, Zhao J, Son Y-J and Luo W (2012) The majority of dorsal spinal cord gastrin releasing peptide is synthesized locally whereas neuromedin B is highly expressed in pain-and itchsensing somatosensory neurons. Mol Pain 8, 52   DOI
70 Sun YG and Chen ZF (2007) A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700-703   DOI
71 Mishra SK and Hoon MA (2013) The cells and circuitry for itch responses in mice. Science 340, 968-971   DOI
72 Sukhtankar DD and Ko MC (2013) Physiological function of gastrin-releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice. PLoS One 8, e67422   DOI
73 Liu XY, Wan L, Huo FQ et al (2014) B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway. Mol Pain 10, 4   DOI
74 McDonald T, Jörnvall H, Nilsson G et al (1979) Characterization of a gastrin releasing peptide from porcine non-antral gastric tissue. Biochem Biophys Res Commun 90, 227-233   DOI
75 Andoh T, Kuwazono T, Lee J-B and Kuraishi Y (2011) Gastrin-releasing peptide induces itch-related responses through mast cell degranulation in mice. Peptides 32, 2098-2103   DOI
76 Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY and Chen ZF (2009) Cellular basis of itch sensation. Science 325, 1531-1534   DOI
77 Wang X, Zhang J, Eberhart D et al (2013) Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron 78, 312-324   DOI
78 Dado RJ, Katter JT and Giesler G (1994) Spinothalamic and spinohypothalamic tract neurons in the cervical enlargement of rats. II. Responses to innocuous and noxious mechanical and thermal stimuli. J Neurophysiol 71, 981-1002   DOI
79 Price DD, Hayes RL, Ruda M and Dubner R (1978) Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J Neurophysiol 41, 933-947   DOI
80 Chudler EH, Foote WE and Poletti CE (1991) Responses of cat C 1 spinal cord dorsal and ventral horn neurons to noxious and non-noxious stimulation of the head and face. Brain Res 555, 181-192   DOI
81 Andrew D and Craig AD (2001) Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat Neurosci 4, 72-77   DOI
82 Davidson S, Zhang X, Khasabov SG et al (2012) Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J Neurophysiol 108, 1711-1723   DOI
83 Akiyama T, Merrill AW, Carstens MI and Carstens E (2009) Activation of superficial dorsal horn neurons in the mouse by a PAR-2 agonist and 5-HT: potential role in itch. J Neurosci 29, 6691-6699   DOI
84 Akiyama T, Carstens MI and Carstens E (2009) Excitation of mouse superficial dorsal horn neurons by histamine and/or PAR-2 agonist: potential role in itch. J Neurophysiol 102, 2176-2183   DOI
85 Akiyama T, Curtis E, Nguyen T, Carstens MI and Carstens E (2016) Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice. J Comp Neurol 524, 244-256   DOI
86 Basbaum AI, Bautista DM, Scherrer G and Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139, 267-284   DOI
87 Keele C (1970) Chemcial Causes of Pain and Itch. Annu Rev Med 21, 67-74   DOI
88 Ballantyne JC, Loach AB and Carr DB (1988) Itching after epidural and spinal opiates. Pain 33, 149-160   DOI
89 Thomas DA, Anton F, Kenshalo DR, Williams GM and Dubner R (1993) Noradrenergic and opioid systems interact to alter the detection of noxious thermal stimuli and facial scratching in monkeys. Pain 55, 63-70   DOI
90 Ständer S and Schmelz M (2006) Chronic itch and pain - Similarities and differences. Eur J Pain 10, 473-478   DOI
91 Green BG and Shaffer GS (1993) The sensory response to capsaicin during repeated topical exposures: differential effects on sensations of itching and pungency. Pain 53, 323-334   DOI
92 Sikand P, Shimada SG, Green BG and LaMotte RH (2011) Sensory responses to injection and punctate application of capsaicin and histamine to the skin. Pain 152, 2485-2494   DOI
93 Simone DA, Baumann TK and LaMotte RH (1989) Dose-dependent pain and mechanical hyperalgesia in humans after intradermal injection of capsaicin. Pain 38, 99-107   DOI
94 Green BG (1990) Spatial summation of chemical irritation and itch produced by topical application of capsaicin. Percept Psychophys 48, 12-18   DOI
95 Wang H, Papoiu A, Coghill R, Patel T, Wang N and Yosipovitch G (2010) Ethnic differences in pain, itch and thermal detection in response to topical capsaicin: African Americans display a notably limited hyperalgesia and neurogenic inflammation. Br J Dermatol 162, 1023-1029   DOI
96 Moser HR and Giesler GJ (2014) Characterization of pruriceptive trigeminothalamic tract neurons in rats. J Neurophysiol 111, 1574-1589   DOI
97 Lagerström MC, Rogoz K, Abrahamsen B et al (2010) VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68, 529-542   DOI
98 Ikoma A, Handwerker H, Miyachi Y and Schmelz M (2005) Electrically evoked itch in humans. Pain 113, 148-154   DOI
99 Tuckett RP (1982) Itch evoked by electrical stimulation of the skin. J Invest Dermatol 79, 368-373   DOI
100 Handwerker H, Forster C and Kirchhoff C (1991) Discharge patterns of human C-fibers induced by itching and burning stimuli. J Neurophysiol 66, 307-315   DOI
101 Braz JM, Juarez-Salinas D, Ross SE and Basbaum AI (2014) Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest 124, 3612-3616   DOI
102 Liu Y, Abdel Samad O, Zhang L et al (2010) VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68, 543-556   DOI
103 Roberson DP, Gudes S, Sprague JM et al (2013) Activity-dependent silencing reveals functionally distinct itch-generating sensory neurons. Nat Neurosci 16, 910-918   DOI
104 Ross SE, Mardinly AR, McCord AE et al (2010) Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886-898   DOI
105 Drzezga A, Darsow U, Treede RD et al (2001) Central activation by histamine-induced itch: analogies to pain processing: a correlational analysis of O-15 H2O positron emission tomography studies. Pain 92, 295-305   DOI
106 Herde L, Forster C, Strupf M and Handwerker HO (2007) Itch induced by a novel method leads to limbic deactivations- A functional MRI study. J Neurophysiol 98, 2347-2356   DOI
107 Mochizuki H, Tashiro M, Kano M, Sakurada Y, Itoh M and Yanai K (2003) Imaging of central itch modulation in the human brain using positron emission tomography. Pain 105, 339-346   DOI
108 Mochizuki H, Sadato N, Saito DN et al (2007) Neural correlates of perceptual difference between itching and pain: A human fMRI study. Neuroimage 36, 706-717   DOI
109 Dum RP, Levinthal DJ and Strick PL (2009) The spinothalamic system targets motor and sensory areas in the cerebral cortex of monkeys. J Neurosci 29, 14223-14235   DOI
110 Apkarian AV and Hodge CJ (1989) A dorsolateral spinothalamic tract in macaque monkey. Pain 37, 323-333   DOI
111 Papoiu AD, Emerson NM, Patel TS et al (2014) Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease. Journal of Neurophysiology 112, 1729-1738   DOI
112 Mochizuki H, Inui K, Tanabe HC et al (2009) Time course of activity in itch-related brain regions: a combined MEG–fMRI study. J Neurophysiol 102, 2657-2666   DOI
113 Leknes SG, Bantick S, Willis CM, Wilkinson JD, Wise RG and Tracey I (2007) Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen- and histamine-induced itch in humans. J Neurophysiol 97, 415-422   DOI
114 Papoiu AD, Coghill RC, Kraft RA, Wang H and Yosipovitch G (2012) A tale of two itches. Common features and notable differences in brain activation evoked by cowhage and histamine induced itch. Neuroimage 59, 3611-3623   DOI
115 Craig AD (2009) How do you feel—now? the anterior insula and human awareness. Nat Rev Neurosci 10, 59-70   DOI
116 Coghill RC, Sang CN, Maisog JM and Iadarola MJ (1999) Pain intensity processing within the human brain: a bilateral, distributed mechanism. J Neurophysiol 82, 1934-1943   DOI
117 Saper CB (1982) Convergence of autonomic and limbic connections in the insular cortex of the rat. J Comp Neurol 210, 163-173   DOI
118 Allen GV, Saper CB, Hurley KM and Cechetto DF (1991) Organization of visceral and limbic connections in the insular cortex of the rat. J Comp Neurol 311, 1-16   DOI
119 Gu X, Hof PR, Friston KJ and Fan J (2013) Anterior insular cortex and emotional awareness. J Comp Neurol 521, 3371-3388   DOI
120 Nieuwenhuys R (2012) The insular cortex: a review. Prog Brain Res 195, 123-163
121 Hsieh JC, Hagermark O, Stahle-Backdahl M et al (1994) Urge to scratch represented in the human cerebral cortex during itch. J Neurophysiol 72, 3004-3008   DOI
122 Fuchs PN, Peng YB, Boyette-Davis JA and Uhelski ML (2014) The anterior cingulate cortex and pain processing. Front Integr Neurosci 8, 35   DOI
123 Iwata K, Kamo H, Ogawa A et al (2005) Anterior cingulate cortical neuronal activity during perception of noxious thermal stimuli in monkeys. J Neurophysiol 94, 1980-1991   DOI
124 Ballantine HT Jr, Cassidy WL, Flanagan NB and Marino R Jr (1967) Stereotaxic anterior cingulotomy for neuropsychiatric illness and intractable pain. J Neurosurg 26,   DOI
125 Ishiuji Y, Coghill RC, Patel TS, Oshiro Y, Kraft RA and Yosipovitch G (2009) Distinct patterns of brain activity evoked by histamine-induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. Br J Dermatol 161, 1072-1080   DOI
126 Papoiu AD, Nattkemper LA, Sanders KM et al (2013) Brain's reward circuits mediate itch relief. A functional MRI study of active scratching. PLoS One 8, e82389   DOI
127 Darsow U, Drzezga A, Frisch M et al (2000) Processing of histamine-induced itch in the human cerebral cortex: a correlation analysis with dermal reactions. J Invest Dermatol 115, 1029-1033   DOI
128 Schneider G, Ständer S, Burgmer M, Driesch G, Heuft G and Weckesser M (2008) Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects. Eur J Pain 12, 834-841   DOI
129 Vierow V, Fukuoka M, Ikoma A, Dörfler A, Handwerker HO and Forster C (2009) Cerebral representation of the relief of itch by scratching. J Neurophysiol 102, 3216-3224   DOI
130 Carrasquillo Y and Gereau RW 4th (2007) Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception. J Neurosci 27, 1543-1551   DOI
131 Mochizuki H, Papoiu AD, Nattkemper LA et al (2015) Scratching induces overactivity in motor-related regions and reward system in chronic itch patients. J Invest Dermatol 135, 2814-2823   DOI
132 Braz J, Solorzano C, Wang X and Basbaum AI (2014) Transmitting pain and itch messages: a contemporary view of the spinal cord circuits that generate gate control. Neuron 82, 522-536   DOI
133 Gauriau C and Bernard JF (2002) Pain pathways and parabrachial circuits in the rat. Exp Physiol 87, 251-258   DOI
134 Neugebauer V (2015) Amygdala pain mechanisms. Handb ExpPharmacol 227, 261-284
135 Veinante P, Yalcin I and Barrot M (2013) The amygdala between sensation and affect: a role in pain. J Mol Psychiatry 1, 9   DOI
136 Gotoh Y, Omori Y, Andoh T and Kuraishi Y (2011) Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice. J Pharmacol Sci 115, 417-420   DOI
137 Chen L, Wang W, Tan T, Han H and Dong Z (2016) GABA(A) receptors in the central nucleus of the amygdala are involved in pain-and itch-related responses. J Pain 17, 181-189   DOI
138 Kleyn CE, McKie S, Ross A, Elliott R and Griffiths CE (2012) A temporal analysis of the central neural processing of itch. Br J Dermatol 166, 994-1001   DOI
139 Akiyama T, Iodi Carstens M and Carstens E (2011) Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli. PLoS One 6, e22665   DOI
140 Barretto RP and Schnitzer MJ (2012) In vivo microendoscopy of the hippocampus. Cold Spring Harb Protoc 2012, 1092-1099
141 Zhao ZQ, Liu XY, Jeffry J et al (2014) Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 84, 821-834   DOI
142 Mochizuki H, Papoiu AD and Yosipovitch G (2014) Itch: Mechanisms and Treatment. CRC Press/Taylor & Francis, Boca Raton, Florida, USA
143 Svoboda K and Yasuda R (2006) Principles of two-photon excitation microscopy and its applications to neuroscience. Neuron 50, 823-839   DOI
144 Deisseroth K (2015) Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18, 1213-1225   DOI
145 Roth BL (2016) DREADDs for neuroscientists. Neuron 89, 683-694   DOI
146 Wickersham IR, Lyon DC, Barnard RJ et al (2007) Monosynaptic restriction of transsynaptic tracing from single, genetically targeted neurons. Neuron 53, 639-647   DOI
147 Papoiu AD, Kraft RA, Coghill RC and Yosipovitch G (2015) Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study. J Invest Dermatol 135, 560-568   DOI
148 Lo L and Anderson DJ (2011) A Cre-dependent, anterograde transsynaptic viral tracer for mapping output pathways of genetically marked neurons. Neuron 72, 938-950   DOI
149 Valet M, Pfab F, Sprenger T et al (2008) Cerebral processing of histamine-induced itch using short-term alternating temperature modulation – An FMRI study. J Invest Dermat 128, 426-433   DOI
150 Pfab F, Valet M, Sprenger T et al (2010) Temperature modulated histamine-itch in lesional and nonlesional skin in atopic eczema – a combined psychophysical and neuroimaging study. Allergy 65, 84-94   DOI
151 Napadow V, Li A, Loggia ML et al (2014) The brain circuitry mediating antipruritic effects of acupuncture. Cereb Cortex 24, 873-882   DOI