Neurobiology of Itch (Pruritus)

Abstract

Itch is often defined as an ‘unpleasant sensation that provokes the desire to scratch’. Recent studies have provided novel insights into the molecular mechanisms underlying itch‐selective signalling pathways from the periphery to the central nervous system. Chronic itch is often associated with inflammatory skin diseases such as atopic dermatitis, psoriasis or contact dermatitis, as well as systemic diseases such as renal, cholestatic, hematologic or endocrine pruritus or pruritus related to malignancy, and reduces quality of life. Chronic itch is thought to involve the sensitisation of itch‐signalling pathways, the molecular and cellular processes of which we are just starting to uncover. This review article describes recent findings regarding the basic mechanisms of itch transmission from the skin to the brain. We further describe the neuronal changes that occur both peripherally and centrally under conditions of chronic itch.

Key Concepts

  • There are a variety of endogenous pruritogens and external itch stimuli.
  • Itch transducing channels include TRPV1, TRPA1 and Nav1.7.
  • Spinal excitatory and inhibitory interneurons process itch information.
  • Descending noradrenergic and serotonergic systems modulate spinal itch transmission.
  • Sensitisation occurs in both peripheral and central nervous system under conditions of chronic itch.
  • NK1‐expressing spinal neurons play a major role in itch sensitisation.

Keywords: itch; pruritus; sodium channels; TRP channels; sensitisation; brain; spinal cord; pruriceptors; descending modulation

Figure 1. Schematic drawing of two distinct peripheral nerve terminals of pruriceptors. TRPA1 is activated downstream of GPCRs stimulated by pruritogens other than histamine. TRPV1 is activated downstream of IL31RA/OSMR or H1/H4R stimulated by IL‐31 or histamine, respectively. Both TRP channels produce depolarisation which can open Nav1.7. Action potentials are generated via Nav1.7 to transmit itch signals. Although Nav1.8 is expressed by pruriceptors, a contribution of Nav1.8 to itch is still unknown.
Figure 2. Schematic diagrams of spinal processing of itch (from reference 5, with permission). (a) Itch‐transmitting primary afferent fibres terminate onto NPRA‐expressing excitatory interneurons. GRPR‐expressing excitatory interneurons receive inputs from NPRA‐expressing excitatory interneurons and make synapses (directly or indirectly) onto NK1R‐expressing projection neurons. NK1‐expressing projection neurons receive inhibitory input from Bhlhb5‐originated inhibitory interneurons via dynorphin as well as GABA and glycine. NK1‐expressing spinal neurons also receive polysynaptic input from NK1‐expressing excitatory interneurons that are located in lamina III and transmit touch signals. This pathway is silenced by GABAergic and glycinergic inhibitory interneurons under normal conditions. Whether these inhibitory interneurons originate from Bhlhb5‐expressing spinal neurons is still unknown. (b) Chronic itch leads to sensitisation of itch signalling pathways. Under the condition of chronic itch, NK1‐expressing projection neurons are hyperexcited. A lower activation threshold of NK1‐expressing projection neurons results in spontaneous itch, touch‐evoked itch (alloknesis) and enhanced itch (hyperknesis). Another potential explanation for itch sensitisation is a dysfunction of itch‐inhibitory interneurons. This dysfunction results in disinhibition of NK1‐expressing projection neurons and possibly the polysynaptic touch pathway that sends signals to NK1‐expressing projection neurons Reproduced with permission from Akiyama et al., (2015) © Wolters Kluwer Health, Inc.
Figure 3. The representative brain regions activated by itch stimuli. Brain regions active during itch are indicated by red on three‐dimensional images of brain templates implemented in the MRIcron software (images of brain templates reproduced from http://www.mccauslandcenter.sc.edu/mricro/mricro/). Abbreviations: SMA, supplementary motor area; PM, premotor cortex; MI, primary motor cortex; SI, primary somatosensory cortex; SII, secondary somatosensory cortex; Cb, cerebellum; dACC, dorsal part of the anterior cingulate cortex; aMCC, anterior part of the midcingulate cortex; PCC, posterior cingulate cortex; Prec, precuneus; IC: insular cortex.
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References

Ahmad S , Dahllund L , Eriksson AB , et al. (2007) A stop codon mutation in SCN9A causes lack of pain sensation. Human Molecular Genetics 16 (17): 2114–2121.

Akiyama T , Carstens MI and Carstens E (2010) Enhanced scratching evoked by PAR‐2 agonist and 5‐HT but not histamine in a mouse model of chronic dry skin itch. Pain 151 (2): 378–383.

Akiyama T , Iodi Carstens M , Carstens E (2011) Transmitters and pathways mediating inhibition of spinal itch‐signaling neurons by scratching and other counterstimuli. PLoS One, 6(7):e22665.

Akiyama T , Tominaga M , Davoodi A , et al. (2012a) Roles for substance P and gastrin releasing peptide as neurotransmitters released by primary afferent pruriceptors. Journal of Neurophysiology 109 (3): 742–748.

Akiyama T , Tominaga M , Davoodi A , et al. (2012b) Cross‐sensitization of histamine‐independent itch in mouse primary sensory neurons. Neuroscience 226: 305–312.

Akiyama T , Carstens MI , Ikoma A , et al. (2012c) Mouse model of touch‐evoked itch (alloknesis). Journal of Investigative Dermatology 132 (7): 1886–1891.

Akiyama T , Tominaga M , Davoodi A , et al. (2013) Roles for substance P and gastrin‐releasing peptide as neurotransmitters released by primary afferent pruriceptors. Journal of Neurophysiology 109 (3): 742–748.

Akiyama T , Tominaga M , Takamori K , Carstens MI and Carstens E (2014) Roles of glutamate, substance P, and gastrin‐releasing peptide as spinal neurotransmitters of histaminergic and nonhistaminergic itch. Pain 155 (1): 80–92.

Akiyama T , Nguyen T , Curtis E , et al. (2015) A central role for spinal dorsal horn neurons that express neurokinin‐1 receptors in chronic itch. Pain 156 (7): 1240–1246.

Alemi F , Kwon E , Poole DP , et al. (2013) The TGR5 receptor mediates bile acid‐induced itch and analgesia. Journal of Clinical Investigation 123 (4): 1513–1530.

Andoh T , Nagasawa T , Satoh M and Kuraishi Y (1998) Substance P induction of itch‐associated response mediated by cutaneous NK1 tachykinin receptors in mice. Journal of Pharmacology and Experimental Therapeutics 286 (3): 1140–1145.

Apkarian AV , Bushnell MC , Treede RD and Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain 9 (4): 463–484.

Bar KJ , Gaser C , Nenadic I and Sauer H (2002) Transient activation of a somatosensory area in painful hallucinations shown by fMRI. Neuroreport 13 (6): 805–808.

Bardoni R , Takazawa T , Tong CK , et al. (2013) Pre‐ and postsynaptic inhibitory control in the spinal cord dorsal horn. The Annals of the New York Academy of Sciences 1279: 90–96.

Bell JK , McQueen DS and Rees JL (2004) Involvement of histamine H4 and H1 receptors in scratching induced by histamine receptor agonists in Balb C mice. British Journal of Pharmacology 142 (2): 374–380.

Bergeret L , Black D , Theunis J , et al. (2011) Validation of a model of itch induction for brain positron emission tomography studies using histamine iontophoresis. Acta Dermato‐Venereologica 91 (5): 504–510.

Bornhovd K , Quante M , Glauche V , et al. (2002) Painful stimuli evoke different stimulus–response functions in the amygdala, prefrontal, insula and somatosensory cortex: a single‐trial fMRI study. Brain 125 (Pt 6): 1326–1336.

Braz JM , Juarez‐Salinas D , Ross SE and Basbaum AI (2014) Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. Journal of Clinical Investigation 124 (8): 3612–3616.

Bush G , Luu P and Posner MI (2000) Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences 4 (6): 215–222.

Carstens EE , Carstens MI , Simons CT and Jinks SL (2010) Dorsal horn neurons expressing NK‐1 receptors mediate scratching in rats. Neuroreport 21 (4): 303–308.

Cevikbas F , Wang X , Akiyama T , et al. (2014) A sensory neuron‐expressed IL‐31 receptor mediates T helper cell‐dependent itch: involvement of TRPV1 and TRPA1. Journal of Allergy and Clinical Immunology 133 (2): 448–460.

Cox JJ , Reimann F , Nicholas AK , et al. (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444 (7121): 894–898.

Craig AD (2010) The sentient self. Brain Structure & Function 214 (5–6): 563–577.

Davidson S , Zhang X , Khasabov SG , et al. (2012) Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. Journal of Neurophysiology 108 (6): 1711–1723.

Devigili G , Eleopra R , Pierro T , et al. (2014) Paroxysmal itch caused by gain‐of‐function Nav1.7 mutation. Pain 155 (9): 1702–1707.

Dillon S , Sprecher C , Hammond A , et al. (2004) Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nature Immunology 5 (7): 752–760.

Dogrul A , Ossipov MH and Porreca F (2009) Differential mediation of descending pain facilitation and inhibition by spinal 5HT‐3 and 5HT‐7 receptors. Brain Research 1280: 52–59.

Dogrul A , Seyrek M , Yalcin B and Ulugol A (2012) Involvement of descending serotonergic and noradrenergic pathways in CB1 receptor‐mediated antinociception. Progress in Neuro‐Psychopharmacology & Biological Psychiatry 38 (1): 97–105.

Dong WK , Salonen LD , Kawakami Y , et al. (1989) Nociceptive responses of trigeminal neurons in SII‐7b cortex of awake monkeys. Brain Research 484 (1–2): 314–324.

Dong WK , Chudler EH , Sugiyama K , Roberts VJ and Hayashi T (1994) Somatosensory, multisensory, and task‐related neurons in cortical area 7b (PF) of unanesthetized monkeys. Journal of Neurophysiology 72 (2): 542–564.

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 (1–2): 295–305.

Dunford PJ , Williams KN , Desai PJ , et al. (2007) Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus. Journal of Allergy and Clinical Immunology 119 (1): 176–183.

Eglezos A , Lecci A , Santicioli P , et al. (1992) Activation of capsaicin‐sensitive primary afferents in the rat urinary bladder by compound 48/80: a direct action on sensory nerves? Archives Internationales de Pharmacodynamie et de Thérapie 315: 96–109.

Ekberg J , Jayamanne A , Vaughan CW , et al. (2006) muO‐conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. Proceedings of the National Academy of Sciences of the United States of America 103 (45): 17030–17035.

Emerson NM , Zeidan F , Lobanov OV , et al. (2014) Pain sensitivity is inversely related to regional grey matter density in the brain. Pain 155 (3): 566–573.

Estacion M , Han C , Choi JS , et al. (2011) Intra‐ and interfamily phenotypic diversity in pain syndromes associated with a gain‐of‐function variant of NaV1.7. Molecular Pain 7: 92.

Faber CG , Hoeijmakers JG , Ahn HS , et al. (2012) Gain of function Nanu1.7 mutations in idiopathic small fiber neuropathy. Annals of Neurology 71 (1): 26–39.

Fertleman CR , Baker MD , Parker KA , et al. (2006) SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron 52 (5): 767–774.

Fried I , Katz A , McCarthy G , et al. (1991) Functional organization of human supplementary motor cortex studied by electrical stimulation. Journal of Neuroscience 11 (11): 3656–3666.

Friedman MA , Fleming LE , Fernandez M , et al. (2008) Ciguatera fish poisoning: treatment, prevention and management. Marine Drugs 6 (3): 456–479.

Fukuoka M , Miyachi Y and Ikoma A (2013) Mechanically evoked itch in humans. Pain 154 (6): 897–904.

Gingras J , Smith S , Matson DJ , Johnson D , Nye K , Couture L , Feric E , Yin R , Moyer BD , Peterson ML , Rottman JB , Beiler RJ , Malmberg AB , McDonough SI . Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain. PLoS One 2014;9(9):e105895.

Goldberg YP , MacFarlane J , MacDonald ML , et al. (2007) Loss‐of‐function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clinical Genetics 71 (4): 311–319.

Gotoh Y , Andoh T and Kuraishi Y (2011) Noradrenergic regulation of itch transmission in the spinal cord mediated by alpha‐adrenoceptors. Neuropharmacology 61 (4): 825–831.

Gu X , Hof PR , Friston KJ and Fan J (2013) Anterior insular cortex and emotional awareness. Journal of Comparative Neurology 521 (15): 3371–3388.

Han L , Ma C , Liu Q , et al. (2013) A subpopulation of nociceptors specifically linked to itch. Nature Neuroscience 16 (2): 174–182.

Hawro T , Fluhr JW , Mengeaud V , et al. (2014) Polidocanol inhibits cowhage – but not histamine‐induced itch in humans. Experimental Dermatology 23 (12): 922–923.

Herde L , Forster C , Strupf M and Handwerker HO (2007) Itch induced by a novel method leads to limbic deactivations a functional MRI study. Journal of Neurophysiology 98 (4): 2347–2356.

Hsieh JC , Hagermark O , Stahle‐Backdahl M , et al. (1994) Urge to scratch represented in the human cerebral cortex during itch. Journal of Neurophysiology 72 (6): 3004–3008.

Huang J , Han C , Estacion M , et al. (2014) Gain‐of‐function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain 137 (Pt 6): 1627–1642.

Ikoma A , Handwerker H , Miyachi Y and Schmelz M (2005) Electrically evoked itch in humans. Pain 113 (1–2): 148–154.

Imamachi N , Park GH , Lee H , et al. (2009) TRPV1‐expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proceedings of the National Academy of Sciences of the United States of America 106 (27): 11330–11335.

Inagaki N , Igeta K , Kim J , et al. (2002) Involvement of unique mechanisms in the induction of scratching behavior in BALB/c mice by compound 48/80. European Journal of Pharmacology 448 (2–3): 175–183.

Ishiuji Y , Coghill RC , Patel TS , et al. (2009) Distinct patterns of brain activity evoked by histamine‐induced itch reveal an association with itch intensity and disease severity in atopic dermatitis. British Journal of Dermatology 161 (5): 1072–1080.

Jansen NA and Giesler GJ Jr (2015) Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat. Journal of Neurophysiology 113: 58–70. DOI: jn 00596 02014.

Johanek LM , Meyer RA , Friedman RM , et al. (2008) A role for polymodal C‐fiber afferents in nonhistaminergic itch. Journal of Neuroscience 28 (30): 7659–7669.

Jones CL , Ward J and Critchley HD (2010) The neuropsychological impact of insular cortex lesions. Journal of Neurology, Neurosurgery and Psychiatry 81 (6): 611–618.

Kalivas PW and Volkow ND (2005) The neural basis of addiction: a pathology of motivation and choice. The American Journal of Psychiatry 162 (8): 1403–1413.

Kardon AP , Polgar E , Hachisuka J , et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82 (3): 573–586.

Katugampola R and Church M (2000) The neurogenic vasodilator response to endothelin‐1: a study in human skin in vivo. Experimental Physiology 85: 839–846.

Kido‐Nakahara M , Buddenkotte J , Kempkes C , et al. (2014) Neural peptidase endothelin‐converting enzyme 1 regulates endothelin 1‐induced pruritus. Journal of Clinical Investigation 124 (6): 2683–2695.

Kim YS , Chu Y , Han L , et al. (2014) Central terminal sensitization of TRPV1 by descending serotonergic facilitation modulates chronic pain. Neuron 81 (4): 873–887.

Klinger AB , Eberhardt M , Link AS , et al. (2012) Sea‐anemone toxin ATX‐II elicits A‐fiber‐dependent pain and enhances resurgent and persistent sodium currents in large sensory neurons. Molecular Pain 8: 69.

Koga K , Chen T , Li XY , et al. (2011) Glutamate acts as a neurotransmitter for gastrin releasing peptide‐sensitive and insensitive itch‐related synaptic transmission in mammalian spinal cord. Molecular Pain 7: 47.

Kollmeier A , Francke K , Chen B , et al. (2014) The histamine H(4) receptor antagonist, JNJ 39758979, is effective in reducing histamine‐induced pruritus in a randomized clinical study in healthy subjects. Journal of Pharmacology and Experimental Therapeutics 350 (1): 181–187.

Lee JH , Park CK , Chen G , et al. (2014) A monoclonal antibody that targets a NaV1.7 channel voltage sensor for pain and itch relief. Cell 157 (6): 1393–1404.

Leknes SG , Bantick S , Willis CM , et al. (2007) Itch and motivation to scratch: an investigation of the central and peripheral correlates of allergen‐ and histamine‐induced itch in humans. Journal of Neurophysiology 97 (1): 415–422.

Lieu T , Jayaweera G , Zhao P , et al. (2014) The bile acid receptor TGR5 activates the TRPA1 channel to induce itch in mice. Gastroenterology 147: 1417–1428.

Lin Z , Chen Q , Lee M , et al. (2012) Exome sequencing reveals mutations in TRPV3 as a cause of Olmsted syndrome. The American Journal of Human Genetics 90 (3): 558–564.

Liu Q , Tang Z , Surdenikova L , et al. (2009) Sensory neuron‐specific GPCR Mrgprs are itch receptors mediating chloroquine‐induced pruritus. Cell 139 (7): 1353–1365.

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 (3): 543–556.

Liu Q , Sikand P , Ma C , et al. (2012) Mechanisms of itch evoked by beta‐alanine. Journal of Neuroscience 32 (42): 14532–14537.

Lopes C , Liu Z , Xu Y and Ma Q (2012) Tlx3 and Runx1 act in combination to coordinate the development of a cohort of nociceptors, thermoceptors, and pruriceptors. Journal of Neuroscience 32 (28): 9706–9715.

Maekawa T , Yamaguchi‐Miyamoto T , Nojima H and Kuraishi Y (2002) Effects of naltrexone on spontaneous itch‐associated responses in NC mice with chronic dermatitis. Japanese Journal of Pharmacology 90 (2): 193–196.

McCoy ES , Taylor‐Blake B , Street SE , et al. (2013) Peptidergic CGRPalpha primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron 78 (1): 138–151.

McQueen DS , Noble MAH and Bond SM (2007) Endothelin‐1 activates ETA receptors to cause reflex scratching in BALB/c mice. British Journal of Pharmacology 151.

Mishra SK and Hoon MA (2013) The cells and circuitry for itch responses in mice. Science 340 (6135): 968–971.

Miyamoto T , Nojima H and Kuraishi Y (2002) Intradermal cholinergic agonists induce itch‐associated response via M3 muscarinic acetylcholine receptors in mice. Japanese Journal of Pharmacology 88 (3): 351–354.

Mochizuki H , Sadato N , Saito DN , et al. (2007) Neural correlates of perceptual difference between itching and pain: a human fMRI study. NeuroImage 36 (3): 706–717.

Mochizuki H , Inui K , Tanabe HC , et al. (2009) Time course of activity in itch‐related brain regions: a combined MEG‐fMRI study. Journal of Neurophysiology 102 (5): 2657–2666.

Mochizuki H , Baumgartner U , Kamping S , et al. (2013) Cortico‐subcortical activation patterns for itch and pain imagery. Pain 154 (10): 1989–1998.

Moser HR and Giesler GJ Jr (2014) Characterization of pruriceptive trigeminothalamic tract neurons in rats. Journal of Neurophysiology 111 (8): 1574–1589.

Nakano T , Andoh T , Tayama M , et al. (2008) Effects of topical application of tacrolimus on acute itch‐associated responses in mice. Biological and Pharmaceutical Bulletin 31 (4): 752–754.

Namer B , Carr R , Johanek LM , et al. (2008) Separate peripheral pathways for pruritus in man. Journal of Neurophysiology 100 (4): 2062–2069.

Nieuwenhury R , Voogd J and Huijzen CV (1988) The Human Brain Central Nervous System. New York: Springer.

Ossipov MH , Dussor GO and Porreca F (2010) Central modulation of pain. Journal of Clinical Investigation 120 (11): 3779–3787.

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 (4): 3611–3623.

Papoiu AD , Emerson NM , Patel TS , et al. (2014a) 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 (7): 1729–1738.

Papoiu AD , Kraft RA , Coghill RC and Yosipovitch G (2014b) Butorphanol suppression of histamine itch is mediated by nucleus accumbens and septal nuclei: a pharmacological fMRI study. Journal of Investigative Dermatology 135: 560–568.

Peier AM , Reeve AJ , Andersson DA , et al. (2002) A heat‐sensitive TRP channel expressed in keratinocytes. Science 296 (5575): 2046–2049.

Polgar E , Sardella TC , Tiong SY , et al. (2013) Functional differences between neurochemically defined populations of inhibitory interneurons in the rat spinal dorsal horn. Pain 154 (12): 2606–2615.

Qu L , Fan N , Ma C , et al. (2014) Enhanced excitability of MRGPRA3‐ and MRGPRD‐positive nociceptors in a model of inflammatory itch and pain. Brain 137 (Pt 4): 1039–1050.

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. Journal of Neuroscience 28 (17): 4331–4335.

Reddy VB , Shimada SG , Sikand P , Lamotte RH and Lerner EA (2010) Cathepsin S elicits itch and signals via protease‐activated receptors. Journal of Investigative Dermatology 130 (5): 1468–1470.

Roberson DP , Gudes S , Sprague JM , et al. (2013) Activity‐dependent silencing reveals functionally distinct itch‐generating sensory neurons. Nature Neuroscience 16 (7): 910–918.

Roesch MR and Olson CR (2003) Impact of expected reward on neuronal activity in prefrontal cortex, frontal and supplementary eye fields and premotor cortex. Journal of Neurophysiology 90 (3): 1766–1789.

Rogoz K , Andersen HH , Lagerstrom MC and Kullander K (2014) Multimodal use of calcitonin gene‐related Peptide and substance p in itch and acute pain uncovered by the elimination of vesicular glutamate transporter 2 from transient receptor potential cation channel subfamily v member 1 neurons. Journal of Neuroscience 34 (42): 14055–14068.

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 (6): 886–898.

Rukwied RR , Main M , Weinkauf B and Schmelz M (2013) NGF sensitizes nociceptors for cowhage‐ but not histamine‐induced itch in human skin. Journal of Investigative Dermatology 133 (1): 268–270.

Samad OA , Tan AM , Cheng X , et al. (2013) Virus‐mediated shRNA knockdown of Na(v)1.3 in rat dorsal root ganglion attenuates nerve injury‐induced neuropathic pain. Molecular Therapy: The Journal of the American Society of Gene Therapy 21 (1): 49–56.

Schmelz M , Hilliges M , Schmidt R , et al. (2003) Active "itch fibers" in chronic pruritus. Neurology 61 (4): 564–566.

Schneider G , Stander S , Burgmer M , et al. (2008) Significant differences in central imaging of histamine‐induced itch between atopic dermatitis and healthy subjects. European Journal of Pain 12 (7): 834–841.

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 (1–2): 66–75.

Steinhoff M , Neisius U , Ikoma A , et al. (2003) Proteinase‐activated receptor‐2 mediates itch: a novel pathway for pruritus in human skin. Journal of Neuroscience 23 (15): 6176–6180.

Sukhtankar DD , Ko MC . Physiological function of gastrin‐releasing peptide and neuromedin B receptors in regulating itch scratching behavior in the spinal cord of mice. PLoS One 2013;8(6):e67422.

Sun YG and Chen ZF (2007) A gastrin‐releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448 (7154): 700–703.

Sun YG , Zhao ZQ , Meng XL , et al. (2009) Cellular basis of itch sensation. Science 325 (5947): 1531–1534.

Than JY , Li L , Hasan R and Zhang X (2013) Excitation and modulation of TRPA1, TRPV1, and TRPM8 channel‐expressing sensory neurons by the pruritogen chloroquine. Journal of Biological Chemistry 288 (18): 12818–12827.

Timmermann L , Ploner M , Haucke K , et al. (2001) Differential coding of pain intensity in the human primary and secondary somatosensory cortex. Journal of Neurophysiology 86 (3): 1499–1503.

Todd AJ , McGill MM and Shehab SA (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. The European Journal of Neuroscience 12 (2): 689–700.

Todd AJ , Puskar Z , Spike RC , et al. (2002) Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance p‐containing afferents and respond to noxious stimulation. Journal of Neuroscience 22 (10): 4103–4113.

Tominaga M , Ozawa S , Tengara S , Ogawa H and Takamori K (2007) Intraepidermal nerve fibers increase in dry skin of acetone‐treated mice. Journal of Dermatological Science 48 (2): 103–111.

Torsney C and MacDermott AB (2006) Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor‐expressing neurons in rat spinal cord. Journal of Neuroscience 26 (6): 1833–1843.

Tuckett RP (1982) Itch evoked by electrical stimulation of the skin. Journal of Investigative Dermatology 79 (6): 368–373.

Ui H , Andoh T , Lee JB , Nojima H and Kuraishi Y (2006) Potent pruritogenic action of tryptase mediated by PAR‐2 receptor and its involvement in anti‐pruritic effect of nafamostat mesilate in mice. European Journal of Pharmacology 530 (1–2): 172–178.

Vetter I , Touska F , Hess A , et al. (2012) Ciguatoxins activate specific cold pain pathways to elicit burning pain from cooling. The EMBO Journal 31 (19): 3795–3808.

Vogt BA (2005) Pain and emotion interactions in subregions of the cingulate gyrus. Nature Reviews Neuroscience 6 (7): 533–544.

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 (2): 312–324.

Waxman SG (2013) Painful Na‐channelopathies: an expanding universe. Trends in Molecular Medicine 19 (7): 406–409.

Wilson SR , Gerhold KA , Bifolck‐Fisher A , et al. (2011) TRPA1 is required for histamine‐independent, Mas‐related G protein‐coupled receptor‐mediated itch. Nature Neuroscience 14 (5): 595–602.

Wilson SR , The L , Batia LM , et al. (2013) The epithelial cell‐derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell 155 (2): 285–295.

Wooten M , Weng HJ , Hartke TV , et al. (2014) Three functionally distinct classes of C‐fibre nociceptors in primates. Nature Communications 5: 4122.

Xu Y , Lopes C , Wende H , et al. (2013) Ontogeny of excitatory spinal neurons processing distinct somatic sensory modalities. Journal of Neuroscience 33 (37): 14738–14748.

Yamaguchi T , Nagasawa T , Satoh M and Kuraishi Y (1999) Itch‐associated response induced by intradermal serotonin through 5‐HT2 receptors in mice. Neuroscience Research 35 (2): 77–83.

Yamamoto‐Kasai E , Imura K , Yasui K , et al. (2012) TRPV3 as a therapeutic target for itch. Journal of Investigative Dermatology 132 (8): 2109–2112.

Yanarates O , Dogrul A , Yildirim V , et al. (2010) Spinal 5‐HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O‐Desmethyltramadol, via activation of descending serotonergic pathways. Anesthesiology 112 (3): 696–710.

Yang Y , Wang Y , Li S , et al. (2004) Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. Journal of Medical Genetics 41 (3): 171–174.

Yoshioka T , Imura K , Asakawa M , et al. (2009) Impact of the Gly573Ser substitution in TRPV3 on the development of allergic and pruritic dermatitis in mice. Journal of Investigative Dermatology 129 (3): 714–722.

Yosipovitch G and Bernhard JD (2013) Clinical practice. Chronic pruritus. The New England Journal of Medicine 368 (17): 1625–1634.

Zhao ZQ , Huo FQ , Jeffry J , et al. (2013) Chronic itch development in sensory neurons requires BRAF signaling pathways. Journal of Clinical Investigation 123 (11): 4769–4780.

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 (4): 821–834.

Zhao ZQ , Wan L , Liu XY , et al. (2014) Cross‐inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission. Journal of Neuroscience 34 (37): 12402–12414.

Further Reading

Akiyama T and Carstens E (2013) Neural processing of itch. Neuroscience 250: 697–714.

Carstens E and Akiyama T (eds) (2014) Itch: mechanisms and treatment. Boca Raton: CRC Press/ Taylor and Francis, 458 pp.

Cowan A and Yosipovitch G (2015) Pharmacology of itch. Handb Exp Pharmacol. 26: 1–382.

Dhand A and Aminoff MJ (2014) The neurology of itch. Brain. 137 (Pt 2): 313–322.

Kremer AE , Feramisco J , Reeh PW , , Beuers PW , and Oude Elferink RP (2014) Receptors, cells and circuits involved in pruritus of systemic disorders. Biochim Biophys Acta. 1842 (7): 869–892.

LaMotte RH , Dong X and Ringkamp M (2014) Sensory neurons and circuits mediating itch. Nat Rev Neurosci.. 15 (1): 19–31.

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How to Cite close
Akiyama, Tasuku, Mochizuki, Hideki, and Carstens, E(Aug 2015) Neurobiology of Itch (Pruritus). In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025792]