1932

Abstract

Chronic, persistent itch is a devastating symptom that causes much suffering. In recent years, there has been great progress made in understanding the molecules, cells, and circuits underlying itch sensation. Once thought to be carried by pain-sensing neurons, itch is now believed to be capable of being transmitted by dedicated sensory labeled lines. Members of the Mas-related G protein–coupled receptor (Mrgpr) family demarcate an itch-specific labeled line in the peripheral nervous system. In the spinal cord, the expression of other proteins identifies additional populations of itch-dedicated sensory neurons. However, as evidence for labeled-line coding has mounted, studies promoting alternative itch-coding strategies have emerged, complicating our understanding of the neural basis of itch. In this review, we cover the molecules, cells, and circuits related to understanding the neural basis of itch, with a focus on the role of Mrgprs in mediating itch sensation.

Keyword(s): DRGitchMas-relatedMrgprpruritusspinal cord
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2017-11-27
2024-03-29
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Literature Cited

  1. Adebayo RA, Sofowora GG, Onayemi O, Udoh SJ, Ajayi AA. 1.  1997. Chloroquine-induced pruritus in malaria fever: contribution of malaria parasitaemia and the effects of prednisolone, niacin, and their combination, compared with antihistamine. Br. J. Clin. Pharmacol. 44:157–61 [Google Scholar]
  2. Akiyama T, Carstens E. 2.  2013. Neural processing of itch. Neuroscience 250:697–714 [Google Scholar]
  3. Akiyama T, Merrill AW, Zanotto K, Carstens MI, Carstens E. 3.  2009. Scratching behavior and Fos expression in superficial dorsal horn elicited by protease-activated receptor agonists and other itch mediators in mice. J. Pharmacol. Exp. Ther. 329:945–51 [Google Scholar]
  4. Andrew D, Craig AD. 4.  2001. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat. Neurosci. 4:72–77 [Google Scholar]
  5. Avula LR, Buckinx R, Alpaerts K, Costagliola A, Adriaensen D. 5.  et al. 2011. The effect of inflammation on the expression and distribution of the MAS-related gene receptors MrgE and MrgF in the murine ileum. Histochem. Cell Biol. 136:569–85 [Google Scholar]
  6. Bader M, Alenina N, Andrade-Navarro MA, Santos RA. 6.  2014. MAS and its related G protein–coupled receptors, Mrgprs. Pharmacol. Rev. 66:1080–105 [Google Scholar]
  7. Barry DM, Li H, Liu XY, Shen KF, Liu XT. 7.  et al. 2016. Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord. Mol. Pain 12:1744806916643724 [Google Scholar]
  8. Bender E, Buist A, Jurzak M, Langlois X, Baggerman G. 8.  et al. 2002. Characterization of an orphan G protein–coupled receptor localized in the dorsal root ganglia reveals adenine as a signaling molecule. PNAS 99:8573–78 [Google Scholar]
  9. Bourane S, Duan B, Koch SC, Dalet A, Britz O. 9.  et al. 2015. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350:550–54 [Google Scholar]
  10. Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J. 10.  et al. 2000. Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288:306–13 [Google Scholar]
  11. Caterina MJ, Rosen TA, Tominaga M, Brake AJ, Julius D. 11.  1999. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398:436–41 [Google Scholar]
  12. Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ. 12.  et al. 2009. Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. PNAS 106:9075–80 [Google Scholar]
  13. Cox PJ, Pitcher T, Trim SA, Bell CH, Qin W, Kinloch RA. 13.  2008. The effect of deletion of the orphan G–protein coupled receptor (GPCR) gene MrgE on pain-like behaviours in mice. Mol. Pain 4:2 [Google Scholar]
  14. Crozier RA, Ajit SK, Kaftan EJ, Pausch MH. 14.  2007. MrgD activation inhibits KCNQ/M-currents and contributes to enhanced neuronal excitability. J. Neurosci. 27:4492–96 [Google Scholar]
  15. Davidson S, Zhang X, Khasabov SG, Moser HR, Honda CN. 15.  et al. 2012. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J. Neurophysiol. 108:1711–23 [Google Scholar]
  16. Davidson S, Zhang X, Khasabov SG, Simone DA, Giesler GJ Jr.. 16.  2009. Relief of itch by scratching: state-dependent inhibition of primate spinothalamic tract neurons. Nat. Neurosci. 12:544–46 [Google Scholar]
  17. Davidson S, Zhang X, Yoon CH, Khasabov SG, Simone DA, Giesler GJ Jr.. 17.  2007. The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J. Neurosci. 27:10007–14 [Google Scholar]
  18. Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ. 18.  2001. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619–32 [Google Scholar]
  19. Ernberg M, Lundeberg T, Kopp S. 19.  2000. Pain and allodynia/hyperalgesia induced by intramuscular injection of serotonin in patients with fibromyalgia and healthy individuals. Pain 85:31–39 [Google Scholar]
  20. Fleming MS, Ramos D, Han SB, Zhao J, Son YJ, Luo W. 20.  2012. The majority of dorsal spinal cord gastrin releasing peptide is synthesized locally whereas neuromedin B is highly expressed in pain- and itch-sensing somatosensory neurons. Mol. Pain 8:52 [Google Scholar]
  21. Fredriksson R, Lagerstrom MC, Lundin LG, Schioth HB. 21.  2003. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63:1256–72 [Google Scholar]
  22. Gmerek DE, Cowan A. 22.  1983. Bombesin—a central mediator of pruritus?. Br. J. Dermatol. 109:239 [Google Scholar]
  23. Green AD, Young KK, Lehto SG, Smith SB, Mogil JS. 23.  2006. Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 124:50–58 [Google Scholar]
  24. Green D, Dong X. 24.  2015. Supporting itch: a new role for astrocytes in chronic itch. Nat. Med. 21:841–42 [Google Scholar]
  25. Guan Y, Liu Q, Tang Z, Raja SN, Anderson DJ, Dong X. 25.  2010. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. PNAS 107:15933–38 [Google Scholar]
  26. Han L, Ma C, Liu Q, Weng HJ, Cui Y. 26.  et al. 2013. A subpopulation of nociceptors specifically linked to itch. Nat. Neurosci. 16:174–82 [Google Scholar]
  27. Han SK, Dong X, Hwang JI, Zylka MJ, Anderson DJ, Simon MI. 27.  2002. Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through the Gαq/11 pathway. PNAS 99:14740–45 [Google Scholar]
  28. Imamachi N, Park GH, Lee H, Anderson DJ, Simon MI. 28.  et al. 2009. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. PNAS 106:11330–35 [Google Scholar]
  29. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM. 29.  et al. 2004. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–65 [Google Scholar]
  30. Kashem SW, Subramanian H, Collington SJ, Magotti P, Lambris JD, Ali H. 30.  2011. G protein coupled receptor specificity for C3a and compound 48/80-induced degranulation in human mast cells: roles of Mas-related genes MrgX1 and MrgX2. Eur. J. Pharmacol. 668:299–304 [Google Scholar]
  31. Klein AH, Iodi Carstens M, McCluskey TS, Blancher G, Simons CT. 31.  et al. 2011. Novel menthol-derived cooling compounds activate primary and second-order trigeminal sensory neurons and modulate lingual thermosensitivity. Chem. Senses 36:649–58 [Google Scholar]
  32. Kotani M, Mollereau C, Detheux M, Le Poul E, Brezillon S. 32.  et al. 2001. Functional characterization of a human receptor for neuropeptide FF and related peptides. Br. J. Pharmacol. 133:138–44 [Google Scholar]
  33. Kroeze WK, Sheffler DJ, Roth BL. 33.  2003. G-protein-coupled receptors at a glance. J. Cell Sci. 116:4867–69 [Google Scholar]
  34. Lagerstrom MC, Rogoz K, Abrahamsen B, Persson E, Reinius B. 34.  et al. 2010. VGLUT2-dependent sensory neurons in the TRPV1 population regulate pain and itch. Neuron 68:529–42 [Google Scholar]
  35. Lagerstrom MC, Schioth HB. 35.  2008. Structural diversity of G protein-coupled receptors and significance for drug discovery. Nat. Rev. Drug Discov. 7:339–57 [Google Scholar]
  36. LaMotte RH, Dong X, Ringkamp M. 36.  2014. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15:19–31 [Google Scholar]
  37. Lembo PM, Grazzini E, Groblewski T, O'Donnell D, Roy MO. 37.  et al. 2002. Proenkephalin A gene products activate a new family of sensory neuron–specific GPCRs. Nat. Neurosci. 5:201–9 [Google Scholar]
  38. Liu Q, Sikand P, Ma C, Tang Z, Han L. 38.  et al. 2012. Mechanisms of itch evoked by β-alanine. J. Neurosci. 32:14532–37 [Google Scholar]
  39. Liu Q, Tang Z, Surdenikova L, Kim S, Patel KN. 39.  et al. 2009. Sensory neuron–specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:1353–65 [Google Scholar]
  40. Liu Q, Weng HJ, Patel KN, Tang Z, Bai H. 40.  et al. 2011. The distinct roles of two GPCRs, MrgprC11 and PAR2, in itch and hyperalgesia. Sci. Signal. 4:ra45 [Google Scholar]
  41. Liu T, Gao YJ, Ji RR. 41.  2012. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci. Bull. 28:131–44 [Google Scholar]
  42. Liu XY, Wan L, Huo FQ, Barry DM, Li H. 42.  et al. 2014. B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP–GRPR signaling pathway. Mol. Pain 10:4 [Google Scholar]
  43. Macpherson LJ, Dubin AE, Evans MJ, Marr F, Schultz PG. 43.  et al. 2007. Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature 445:541–45 [Google Scholar]
  44. McNeil BD, Pundir P, Meeker S, Han L, Undem BJ. 44.  et al. 2015. Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature 519:237–41 [Google Scholar]
  45. Melzack R, Wall PD. 45.  1965. Pain mechanisms: a new theory. Science 150:971–79 [Google Scholar]
  46. Mishra SK, Hoon MA. 46.  2013. The cells and circuitry for itch responses in mice. Science 340:968–71 [Google Scholar]
  47. Mollereau C, Mazarguil H, Marcus D, Quelven I, Kotani M. 47.  et al. 2002. Pharmacological characterization of human NPFF1 and NPFF2 receptors expressed in CHO cells by using NPY Y1 receptor antagonists. Eur. J. Pharmacol. 451:245–56 [Google Scholar]
  48. Patel KN, Dong X. 48.  2010. An itch to be scratched. Neuron 68:334–39 [Google Scholar]
  49. Rau KK, McIlwrath SL, Wang H, Lawson JJ, Jankowski MP. 49.  et al. 2009. Mrgprd enhances excitability in specific populations of cutaneous murine polymodal nociceptors. J. Neurosci. 29:8612–19 [Google Scholar]
  50. Reddy VB, Iuga AO, Shimada SG, LaMotte RH, Lerner EA. 50.  2008. Cowhage-evoked itch is mediated by a novel cysteine protease: a ligand of protease-activated receptors. J. Neurosci. 28:4331–35 [Google Scholar]
  51. Reddy VB, Sun S, Azimi E, Elmariah SB, Dong X, Lerner EA. 51.  2015. Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs. Nat. Commun. 6:7864 [Google Scholar]
  52. Ross SE, Mardinly AR, McCord AE, Zurawski J, Cohen S. 52.  et al. 2010. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65:886–98 [Google Scholar]
  53. Roumy M, Zajac JM. 53.  1998. Neuropeptide FF, pain and analgesia. Eur. J. Pharmacol. 345:1–11 [Google Scholar]
  54. Schmelz M, Schmidt R, Weidner C, Hilliges M, Torebjork HE, Handwerker HO. 54.  2003. Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens. J. Neurophysiol. 89:2441–48 [Google Scholar]
  55. Schwendinger-Schreck J, Wilson SR, Bautista DM. 55.  2015. Interactions between keratinocytes and somatosensory neurons in itch. Handb. Exp. Pharmacol. 226:177–90 [Google Scholar]
  56. Shimada SG, LaMotte RH. 56.  2008. Behavioral differentiation between itch and pain in mouse. Pain 139:681–87 [Google Scholar]
  57. Shinohara T, Harada M, Ogi K, Maruyama M, Fujii R. 57.  et al. 2004. Identification of a G protein–coupled receptor specifically responsive to β-alanine. J. Biol. Chem. 279:23559–64 [Google Scholar]
  58. Shiratori-Hayashi M, Koga K, Tozaki-Saitoh H, Kohro Y, Toyonaga H. 58.  et al. 2015. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat. Med. 21:927–31 [Google Scholar]
  59. Sikand P, Dong X, LaMotte RH. 59.  2011. BAM8–22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J. Neurosci. 31:7563–67 [Google Scholar]
  60. Simone DA, Zhang X, Li J, Zhang JM, Honda CN. 60.  et al. 2004. Comparison of responses of primate spinothalamic tract neurons to pruritic and algogenic stimuli. J. Neurophysiol. 91:213–22 [Google Scholar]
  61. Solinski HJ, Gudermann T, Breit A. 61.  2014. Pharmacology and signaling of MAS-related G protein–coupled receptors. Pharmacol. Rev. 66:570–97 [Google Scholar]
  62. Solorzano C, Villafuerte D, Meda K, Cevikbas F, Braz J. 62.  et al. 2015. Primary afferent and spinal cord expression of gastrin-releasing peptide: message, protein, and antibody concerns. J. Neurosci. 35:648–57 [Google Scholar]
  63. Sommer C. 63.  2004. Serotonin in pain and analgesia: actions in the periphery. Mol. Neurobiol. 30:117–25 [Google Scholar]
  64. Subramanian H, Gupta K, Guo Q, Price R, Ali H. 64.  2011. Mas-related gene X2 (MrgX2) is a novel G protein–coupled receptor for the antimicrobial peptide LL-37 in human mast cells: resistance to receptor phosphorylation, desensitization, and internalization. J. Biol. Chem. 286:44739–49 [Google Scholar]
  65. Subramanian H, Kashem SW, Collington SJ, Qu H, Lambris JD, Ali H. 65.  2011. PMX-53 as a dual CD88 antagonist and an agonist for Mas-related gene 2 (MrgX2) in human mast cells. Mol. Pharmacol. 79:1005–13 [Google Scholar]
  66. Sun S, Xu Q, Guo C, Guan Y, Liu Q, Dong X. 66.  2017. Leaky gate model: intensity-dependent coding of pain and itch in the spinal cord. Neuron 93:840–53 [Google Scholar]
  67. Sun YG, Chen ZF. 67.  2007. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448:700–3 [Google Scholar]
  68. Sun YG, Zhao ZQ, Meng XL, Yin J, Liu XY, Chen ZF. 68.  2009. Cellular basis of itch sensation. Science 325:1531–34 [Google Scholar]
  69. Tatemoto K, Nozaki Y, Tsuda R, Konno S, Tomura K. 69.  et al. 2006. Immunoglobulin E-independent activation of mast cell is mediated by Mrg receptors. Biochem. Biophys. Res. Commun. 349:1322–28 [Google Scholar]
  70. Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N. 70.  et al. 2012. Mast cells and inflammation. Biochim. Biophys. Acta 1822:21–33 [Google Scholar]
  71. Usoskin D, Furlan A, Islam S, Abdo H, Lonnerberg P. 71.  et al. 2015. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat. Neurosci. 18:145–53 [Google Scholar]
  72. Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ. 72.  2013. Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493:669–73 [Google Scholar]
  73. Wang H, Zylka MJ. 73.  2009. Mrgprd-expressing polymodal nociceptive neurons innervate most known classes of substantia gelatinosa neurons. J. Neurosci. 29:13202–9 [Google Scholar]
  74. Weisshaar E, Dalgard F. 74.  2009. Epidemiology of itch: adding to the burden of skin morbidity. Acta Derm. Venereol. 89:339–50 [Google Scholar]
  75. Wilson SR, Gerhold KA, Bifolck-Fisher A, Liu Q, Patel KN. 75.  et al. 2011. TRPA1 is required for histamine-independent, Mas-related G protein–coupled receptor–mediated itch. Nat. Neurosci. 14:595–602 [Google Scholar]
  76. Zhang L, Taylor N, Xie Y, Ford R, Johnson J. 76.  et al. 2005. Cloning and expression of MRG receptors in macaque, mouse, and human. Mol. Brain Res. 133:187–97 [Google Scholar]
  77. Zhao ZQ, Huo FQ, Jeffry J, Hampton L, Demehri S. 77.  et al. 2013. Chronic itch development in sensory neurons requires BRAF signaling pathways. J. Clin. Investig. 123:4769–80 [Google Scholar]
  78. Zylka MJ, Dong X, Southwell AL, Anderson DJ. 78.  2003. Atypical expansion in mice of the sensory neuron-specific Mrg G protein–coupled receptor family. PNAS 100:10043–48 [Google Scholar]
  79. Zylka MJ, Rice FL, Anderson DJ. 79.  2005. Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25 [Google Scholar]
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