Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Central neural circuits underlying itch sensation

Nature Reviews Neuroscience volume 26, pages 765–777 (2025)Cite this article

Subjects

Abstract

Itch represents an important somatosensory defensive mechanism. Both mechanical and chemical pruritic stimuli evoke the sensation of itch, and the molecular mechanisms for its peripheral signal transduction have been revealed. Local neuronal networks in the spinal cord are essential for central processing and gating of these transduced itch signals, which are then transmitted to the brain via several types of spinal projection neuron. Both the thalamus and the parabrachial nucleus are essential for the central relay of itch information. In the brain, several neural circuits between brain areas can use this encoded information to alter affective states, which in turn motivate defensive responses such as scratching behaviour. Itch signal processing in the spinal cord is regulated by both neuromodulatory systems and descending pathways. In this Review, progress in the understanding of the neural circuits that underlie itch signal processing, transmission and encoding within the CNS is synthesized. Neural circuit mechanisms in the brain for itch perception and the modulation of itch processing in the spinal cord via descending and neuromodulatory pathways are also discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The local spinal circuit for itch signal processing.
Fig. 2: The ascending pathways for itch signal transmission.
Fig. 3: Brain circuits for itch perception.
Fig. 4: Descending pathways for itch modulation.

Similar content being viewed by others

References

  1. Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G. & Schmelz, M. The neurobiology of itch. Nat. Rev. Neurosci. 7, 535–547 (2006).

    PubMed  CAS  Google Scholar 

  2. Dong, X. & Dong, X. Peripheral and central mechanisms of itch. Neuron 98, 482–494 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Misery, L. et al. Neuropathic pruritus. Nat. Rev. Neurol. 10, 408–416 (2014).

    PubMed  Google Scholar 

  4. Yosipovitch, G. & Samuel, L. S. Neuropathic and psychogenic itch. Dermatol. Ther. 21, 32–41 (2008).

    PubMed  Google Scholar 

  5. Sanders, K. M. & Akiyama, T. The vicious cycle of itch and anxiety. Neurosci. Biobehav. Rev. 87, 17–26 (2018).

    PubMed  PubMed Central  Google Scholar 

  6. Lay, M. & Dong, X. Neural mechanisms of itch. Annu. Rev. Neurosci. 43, 187–205 (2020).

    PubMed  CAS  Google Scholar 

  7. LaMotte, R. H., Dong, X. & Ringkamp, M. Sensory neurons and circuits mediating itch. Nat. Rev. Neurosci. 15, 19–31 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Kim, H., Shim, W. S. & Oh, U. Anoctamin 1, a multi-modal player in pain and itch. Cell Calcium 123, 102924 (2024).

    PubMed  CAS  Google Scholar 

  9. Hill, R. Z., Loud, M. C., Dubin, A. E., Peet, B. & Patapoutian, A. PIEZO1 transduces mechanical itch in mice. Nature 607, 104–110 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  10. Wang, K., Cai, B., Song, Y., Chen, Y. & Zhang, X. Somatosensory neuron types and their neural networks as revealed via single-cell transcriptomics. Trends Neurosci. 46, 654–666 (2023).

    PubMed  CAS  Google Scholar 

  11. von Buchholtz, L. J. et al. Decoding cellular mechanisms for mechanosensory discrimination. Neuron 109, 285–298.e5 (2021).

    Google Scholar 

  12. Chen, X. J. & Sun, Y. G. Central circuit mechanisms of itch. Nat. Commun. 11, 3052 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Mu, D. & Sun, Y. G. Circuit mechanisms of itch in the brain. J. Investig. Dermatol 142, 23–30 (2022).

    PubMed  CAS  Google Scholar 

  14. Liu, M. Z. et al. Synaptic control of spinal GRPR+ neurons by local and long-range inhibitory inputs. Proc. Natl Acad. Sci. USA 116, 27011–27017 (2019).

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Bourane, S. et al. Gate control of mechanical itch by a subpopulation of spinal cord interneurons. Science 350, 550–554 (2015). This study identified a subpopulation of GABAergic neurons that is critical for gating mechanical itch processing in the spinal cord.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Ross, S. E. et al. Loss of inhibitory interneurons in the dorsal spinal cord and elevated itch in Bhlhb5 mutant mice. Neuron 65, 886–898 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Mu, D. et al. A central neural circuit for itch sensation. Science 357, 695–699 (2017). This study demonstrated the critical role of spinoparabrachial pathway in transmitting chemical itch signals to the brain.

    PubMed  CAS  Google Scholar 

  18. Ren, X. et al. Identification of an essential spinoparabrachial pathway for mechanical itch. Neuron 111, 1812–1829.e6 (2023). This study revealed the identity of spinal projection neurons that are critical for mechanical itch and illustrated the ascending pathway for mechanical itch.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. Su, X. Y. et al. Central processing of itch in the midbrain reward center. Neuron 102, 858–872.e5 (2019).

    PubMed  CAS  Google Scholar 

  20. Zheng, J. et al. An insular cortical circuit required for itch sensation and aversion. Curr. Biol. 34, 1453–1468.e6 (2024).

    PubMed  CAS  Google Scholar 

  21. Sun, Y. G. et al. Cellular basis of itch sensation. Science 325, 1531–1534 (2009). This study identified a key population of spinal neurons that is essential for chemical itch signal processing.

    PubMed  CAS  Google Scholar 

  22. Polgar, E. et al. Grpr expression defines a population of superficial dorsal horn vertical cells that have a role in both itch and pain. Pain 164, 149–170 (2023).

    PubMed  CAS  Google Scholar 

  23. Cowan, A., Khunawat, P., Zhu, X. Z. & Gmerek, D. E. Effects of bombesin on behavior. Life Sci. 37, 135–145 (1985).

    PubMed  CAS  Google Scholar 

  24. Kiguchi, N. et al. Functional roles of neuromedin B and gastrin-releasing peptide in regulating itch and pain in the spinal cord of non-human primates. Biochem. Pharmacol. 198, 114972 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  25. Takanami, K. et al. Characterization of the expression of gastrin-releasing peptide and its receptor in the trigeminal and spinal somatosensory systems of Japanese macaque monkeys: insight into humans. J. Comp. Neurol. 530, 2804–2819 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Sun, Y. G. & Chen, Z. F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature 448, 700–703 (2007).

    PubMed  CAS  Google Scholar 

  27. Quillet, R. et al. Synaptic circuits involving gastrin-releasing peptide receptor-expressing neurons in the dorsal horn of the mouse spinal cord. Front. Mol. Neurosci. 16, 1294994 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  28. Mishra, S. K. & Hoon, M. A. The cells and circuitry for itch responses in mice. Science 340, 968–971 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  29. Barry, D. M. et al. Exploration of sensory and spinal neurons expressing gastrin-releasing peptide in itch and pain related behaviors. Nat. Commun. 11, 1397 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Fatima, M. et al. Spinal somatostatin-positive interneurons transmit chemical itch. Pain 160, 1166–1174 (2019).

    PubMed  CAS  Google Scholar 

  31. Sheahan, T. D. et al. Kappa opioids inhibit spinal output neurons to suppress itch. Sci. Adv. 10, eadp6038 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  32. Kardon, A. P. et al. Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82, 573–586 (2014).

    PubMed  PubMed Central  CAS  Google Scholar 

  33. Russ, D. E. et al. A harmonized atlas of mouse spinal cord cell types and their spatial organization. Nat. Commun. 12, 5722 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Brewer, C. L., Styczynski, L. M., Serafin, E. K. & Baccei, M. L. Postnatal maturation of spinal dynorphin circuits and their role in somatosensation. Pain 161, 1906–1924 (2020).

    PubMed  PubMed Central  Google Scholar 

  35. Huang, J. et al. Circuit dissection of the role of somatostatin in itch and pain. Nat. Neurosci. 21, 707–716 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  36. Mona, B. et al. Positive autofeedback regulation of Ptf1a transcription generates the levels of PTF1A required to generate itch circuit neurons. Genes Dev. 34, 621–636 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Boyle, K. A. et al. Neuropeptide Y-expressing dorsal horn inhibitory interneurons gate spinal pain and itch signalling. eLife 12, RP86633 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Foster, E. et al. Targeted ablation, silencing, and activation establish glycinergic dorsal horn neurons as key components of a spinal gate for pain and itch. Neuron 85, 1289–1304 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Escalante, A. & Klein, R. Spinal inhibitory Ptf1a-derived neurons prevent self-generated itch. Cell Rep. 33, 108422 (2020).

    PubMed  CAS  Google Scholar 

  40. Pan, H. et al. Identification of a spinal circuit for mechanical and persistent spontaneous itch. Neuron 103, 1135–1149.e6 (2019). This study identified a key population of spinal neurons that is essential for mechanical itch signal processing.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Acton, D. et al. Spinal neuropeptide Y1 receptor-expressing neurons form an essential excitatory pathway for mechanical itch. Cell Rep. 28, 625–639.e6 (2019). This study identified another key population of spinal neurons that is essential for mechanical itch signal processing.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Xu, J. F. et al. Spinal Nmur2-positive neurons play a crucial role in mechanical itch. J. Pain 25, 104504 (2024).

    PubMed  CAS  Google Scholar 

  43. Chen, S. et al. A spinal neural circuitry for converting touch to itch sensation. Nat. Commun. 11, 5074 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Feng, J. et al. Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch. Science 360, 530–533 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  45. Nelson, T. S. et al. Alleviation of neuropathic pain with neuropeptide Y requires spinal Npy1r interneurons that coexpress Grp. JCI Insight 8, e169554 (2023).

    PubMed  PubMed Central  Google Scholar 

  46. Chen, S. et al. Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling. Mol. Pain 20, 17448069241242982 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Lee, H. et al. Molecular determinants of mechanical itch sensitization in chronic itch. Front. Mol. Neurosci. 15, 937890 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  48. Dai, D. et al. The plasticity of neuropeptide Y-Y1 receptor system on Tac2 neurons contributes to mechanical hyperknesis during chronic itch. Theranostics 14, 363–378 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Al-Khater, K. M., Kerr, R. & Todd, A. J. A quantitative study of spinothalamic neurons in laminae I, III, and IV in lumbar and cervical segments of the rat spinal cord. J. Comp. Neurol. 511, 1–18 (2008).

    PubMed  PubMed Central  Google Scholar 

  50. Wang, L. H., Ding, W. Q. & Sun, Y. G. Spinal ascending pathways for somatosensory information processing. Trends Neurosci. 45, 594–607 (2022).

    PubMed  CAS  Google Scholar 

  51. Bell, A. M. et al. Deep sequencing of Phox2a nuclei reveals five classes of anterolateral system neurons. Proc. Natl Acad. Sci. USA 121, e2314213121 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  52. Ding, W. Q. et al. Single-neuron projectome reveals organization of somatosensory ascending pathways in the mouse brain. Neuron 113, 2083–2101.e5 (2025).

    PubMed  CAS  Google Scholar 

  53. Davidson, S. et al. Pruriceptive spinothalamic tract neurons: physiological properties and projection targets in the primate. J. Neurophysiol. 108, 1711–1723 (2012).

    PubMed  PubMed Central  Google Scholar 

  54. Andrew, D. & Craig, A. D. Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nat. Neurosci. 4, 72–77 (2001).

    PubMed  CAS  Google Scholar 

  55. Davidson, S. et al. The itch-producing agents histamine and cowhage activate separate populations of primate spinothalamic tract neurons. J. Neurosci. 27, 10007–10014 (2007).

    PubMed  PubMed Central  CAS  Google Scholar 

  56. Akiyama, T., Carstens, M. I. & Carstens, E. Excitation of mouse superficial dorsal horn neurons by histamine and/or PAR-2 agonist: potential role in itch. J. Neurophysiol. 102, 2176–2183 (2009).

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Lipshetz, B. et al. Responses of thalamic neurons to itch- and pain-producing stimuli in rats. J. Neurophysiol. 120, 1119–1134 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  58. Jansen, N. A. & Giesler, G. J. Jr Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat. J. Neurophysiol. 113, 58–70 (2015).

    PubMed  Google Scholar 

  59. Li, J. N. et al. Central medial thalamic nucleus dynamically participates in acute itch sensation and chronic itch-induced anxiety-like behavior in male mice. Nat. Commun. 14, 2539 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  60. Choi, S. et al. Parallel ascending spinal pathways for affective touch and pain. Nature 587, 258–263 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  61. Carstens, E. E., Carstens, M. I., Simons, C. T. & Jinks, S. L. Dorsal horn neurons expressing NK-1 receptors mediate scratching in rats. Neuroreport 21, 303–308 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  62. Akiyama, T. et al. A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156, 1240–1246 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  63. Osseward, P. J. 2nd et al. Conserved genetic signatures parcellate cardinal spinal neuron classes into local and projection subsets. Science 372, 385–393 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Haring, M. et al. Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types. Nat. Neurosci. 21, 869–880 (2018).

    PubMed  Google Scholar 

  65. Wercberger, R., Braz, J. M., Weinrich, J. A. & Basbaum, A. I. Pain and itch processing by subpopulations of molecularly diverse spinal and trigeminal projection neurons. Proc. Natl Acad. USA 118, e2105732118 (2021).

    CAS  Google Scholar 

  66. Pauli, J. L. et al. Molecular and anatomical characterization of parabrachial neurons and their axonal projections. eLife 11, e81868 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  67. Liu, P. F. et al. Modulation of itch and pain signals processing in ventrobasal thalamus by thalamic reticular nucleus. iScience 25, 103625 (2022).

    PubMed  CAS  Google Scholar 

  68. Schneider, G. et al. Significant differences in central imaging of histamine-induced itch between atopic dermatitis and healthy subjects. Eur. J. Pain 12, 834–841 (2008).

    PubMed  CAS  Google Scholar 

  69. Mochizuki, H. & Kakigi, R. Central mechanisms of itch. Clin. Neurophysiol. 126, 1650–1660 (2015).

    PubMed  Google Scholar 

  70. Chen, W. Z. et al. An atlas of itch-associated neural dynamics in the mouse brain. Cell Rep. 42, 113304 (2023).

    PubMed  CAS  Google Scholar 

  71. Chen, X. J., Liu, Y. H., Xu, N. L. & Sun, Y. G. Itch perception is reflected by neuronal ignition in the primary somatosensory cortex. Natl Sci. Rev. 9, nwab218 (2022).

    PubMed  CAS  Google Scholar 

  72. Khasabov, S. G. et al. Responses of neurons in the primary somatosensory cortex to itch- and pain-producing stimuli in rats. J. Neurophysiol. 123, 1944–1954 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  73. Woo, S. et al. Multiplexed representation of itch and pain and their interaction in the primary somatosensory cortex. Exp. Neurobiol. 31, 324–331 (2022).

    PubMed  PubMed Central  Google Scholar 

  74. Chen, X. J., Liu, Y. H., Xu, N. L. & Sun, Y. G. Multiplexed representation of itch and mechanical and thermal sensation in the primary somatosensory cortex. J. Neurosci. 41, 10330–10340 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  75. Ran, C., Hoon, M. A. & Chen, X. The coding of cutaneous temperature in the spinal cord. Nat. Neurosci. 19, 1201–1209 (2016).

    PubMed  PubMed Central  CAS  Google Scholar 

  76. Wang, F. et al. Sensory afferents use different coding strategies for heat and cold. Cell Rep. 23, 2001–2013 (2018).

    PubMed  CAS  Google Scholar 

  77. Guo, R. et al. The parietal association cortex and its projections to the dorsal striatum are involved in histaminergic and nonhistaminergic itch processing. Brain Res. Bull. 226, 111352 (2025).

    PubMed  CAS  Google Scholar 

  78. Wu, G. Y. et al. The prelimbic cortex regulates itch processing by controlling attentional bias. iScience 26, 105829 (2023).

    PubMed  Google Scholar 

  79. Gao, F. et al. A non-canonical retina-ipRGCs-SCN-PVT visual pathway for mediating contagious itch behavior. Cell Rep. 41, 111444 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  80. Yu, Y. Q., Barry, D. M., Hao, Y., Liu, X. T. & Chen, Z. F. Molecular and neural basis of contagious itch behavior in mice. Science 355, 1072–1076 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  81. Mu, D. & Sun, Y. G. Itch induces conditioned place aversion in mice. Neurosci. Lett. 658, 91–96 (2017).

    PubMed  CAS  Google Scholar 

  82. Chiang, M. C. et al. Divergent neural pathways emanating from the lateral parabrachial nucleus mediate distinct components of the pain response. Neuron 106, 927–939.e5 (2020).

    PubMed  CAS  Google Scholar 

  83. Pan, Q. et al. Representation and control of pain and itch by distinct prefrontal neural ensembles. Neuron 111, 2414–2431.e7 (2023).

    PubMed  CAS  Google Scholar 

  84. Mochizuki, H., Hernandez, L., Yosipovitch, G., Sadato, N. & Kakigi, R. The amygdala network for processing itch in human brains. Acta Derm. Venereol. 100, adv00345 (2020).

    PubMed  Google Scholar 

  85. Samineni, V. K. et al. Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala. eLife 10, e68130 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  86. Teng, J. F. et al. The projection from the rostral anterior cingulate cortex to the ventral tegmental area regulates 5-HT-induced itch aversion and scratching in rats. Neurobiol. Dis. 207, 106844 (2025).

    PubMed  CAS  Google Scholar 

  87. Yeom, M. et al. Atopic dermatitis induces anxiety- and depressive-like behaviors with concomitant neuronal adaptations in brain reward circuits in mice. Prog. Neuropsychopharmacol. Biol. Psychiatry 98, 109818 (2020).

    PubMed  Google Scholar 

  88. Pavlenko, D. & Akiyama, T. Why does stress aggravate itch? A possible role of the amygdala. Exp. Dermatol. 28, 1439–1441 (2019).

    PubMed  PubMed Central  Google Scholar 

  89. Guo, S. S. et al. A thalamic nucleus reuniens-lateral septum-lateral hypothalamus circuit for comorbid anxiety-like behaviors in chronic itch. Sci. Adv. 10, eadn6272 (2024). This study demonstrated a neural pathway that is involved in anxiety induced by chronic itch.

    PubMed  PubMed Central  CAS  Google Scholar 

  90. Mochizuki, H. et al. The cerebral representation of scratching-induced pleasantness. J. Neurophysiol. 111, 488–498 (2014).

    PubMed  Google Scholar 

  91. Papoiu, A. D. et al. Brain’s reward circuits mediate itch relief. A functional MRI study of active scratching. PLoS One 8, e82389 (2013).

    PubMed  PubMed Central  Google Scholar 

  92. Liang, T. Y., Zhou, H. & Sun, Y. G. Distinct roles of dopamine receptor subtypes in the nucleus accumbens during itch signal processing. J. Neurosci. 42, 8842–8854 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  93. Zhao, Z. Q. et al. Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 84, 821–834 (2014). This study illustrated the mechanism underlying the descending control of spinal itch processing by 5-HT neurons.

    PubMed  PubMed Central  CAS  Google Scholar 

  94. Lesch, K. P. & Waider, J. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron 76, 175–191 (2012).

    PubMed  CAS  Google Scholar 

  95. Chen, Y.-B. et al. Serotoninergic projection from dorsal raphe nucleus to insular cortex is involved in acute itch sensation processing in mice. Brain Res. 1715, 224–234 (2019).

    PubMed  CAS  Google Scholar 

  96. Zhang, Z. J. et al. Descending dopaminergic pathway facilitates itch signal processing via activating spinal GRPR+ neurons. EMBO Rep. 24, e56098 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

  97. Akimoto, Y. & Furuse, M. SCH23390, a dopamine D1 receptor antagonist, suppressed scratching behavior induced by compound 48/80 in mice. Eur. J. Pharmacol. 670, 162–167 (2011).

    PubMed  CAS  Google Scholar 

  98. Rosenzweig-Lipson, S., Hesterberg, P. & Bergman, J. Observational studies of dopamine D1 and D2 agonists in squirrel monkeys. Psychopharmacology 116, 9–18 (1994).

    PubMed  CAS  Google Scholar 

  99. Koga, K. et al. Intrinsic braking role of descending locus coeruleus noradrenergic neurons in acute and chronic itch in mice. Mol. Brain 13, 144 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  101. Gotoh, Y., Omori, Y., Andoh, T. & Kuraishi, Y. Tonic inhibition of allergic itch signaling by the descending noradrenergic system in mice. J. Pharmacol. Sci. 115, 417–420 (2011).

    PubMed  CAS  Google Scholar 

  102. Shiraishi, Y. et al. α1A-Adrenaline receptors in dorsal horn inhibitory neurons have an inhibitory role in the regulation of chloroquine-induced itch in mice. Mol. Brain 14, 55 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  103. Koga, K. et al. Ascending noradrenergic excitation from the locus coeruleus to the anterior cingulate cortex. Mol. Brain 13, 49 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  104. Zhanmu, O. Y. et al. Differential regulation of pruritic sensation and emotion by cannabinoid type 1 receptors on mPFC glutamatergic and GABAergic neurons. Acta Pharmacol. Sin. 46, 904–921 (2025).

    PubMed  CAS  Google Scholar 

  105. Liu, X. Y. et al. Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147, 447–458 (2011).

    PubMed  PubMed Central  CAS  Google Scholar 

  106. Zhou, X. et al. Genetic variation A118G in the OPRM1 gene underlies the dimorphic response to epidural opioid-induced itch. Neurosci. Bull. https://doi.org/10.1007/s12264-025-01411-6 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Nguyen, E. et al. Morphine acts on spinal dynorphin neurons to cause itch through disinhibition. Sci. Transl. Med. 13, eabc3774 (2021).

    PubMed  CAS  Google Scholar 

  108. Wang, Z. et al. Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. Brain 144, 665–681 (2021).

    PubMed  Google Scholar 

  109. Zeng, Q. et al. Neuropeptide Y neurons mediate opioid-induced itch by disinhibiting GRP-GRPR microcircuits in the spinal cord. Nat. Commun. 16, 7074 (2025).

    PubMed  PubMed Central  CAS  Google Scholar 

  110. Smith, K. M., Nguyen, E. & Ross, S. E. The delta-opioid receptor bidirectionally modulates itch. J. Pain 24, 264–272 (2023).

    PubMed  CAS  Google Scholar 

  111. Wu, Z. H. et al. Descending modulation of spinal itch transmission by primary somatosensory cortex. Neurosci. Bull. 37, 1345–1350 (2021).

    PubMed  PubMed Central  Google Scholar 

  112. Liu, Y. et al. Touch and tactile neuropathic pain sensitivity are set by corticospinal projections. Nature 561, 547–550 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  113. Li, J. et al. Cell type-specific modulation of acute itch processing in the anterior cingulate cortex. Adv. Sci. 11, e2403445 (2024).

    Google Scholar 

  114. Lu, Y. C. et al. ACC to dorsal medial striatum inputs modulate histaminergic itch sensation. J. Neurosci. 38, 3823–3839 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  115. Samineni, V. K., Grajales-Reyes, J. G., Sundaram, S. S., Yoo, J. J. & Gereau, R. W. 4th Cell type-specific modulation of sensory and affective components of itch in the periaqueductal gray. Nat. Commun. 10, 4356 (2019).

    PubMed  PubMed Central  Google Scholar 

  116. Wu, G. Y. et al. An excitatory neural circuit for descending inhibition of itch processing. Cell Rep. 43, 115062 (2024).

    PubMed  CAS  Google Scholar 

  117. Gao, Z. R. et al. Tac1-expressing neurons in the periaqueductal gray facilitate the itch-scratching cycle via descending regulation. Neuron 101, 45–59.e9 (2019).

    PubMed  CAS  Google Scholar 

  118. Follansbee, T. et al. Inhibition of itch by neurokinin 1 receptor (Tacr1)-expressing ON cells in the rostral ventromedial medulla in mice. eLife 11, e69626 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  119. Nguyen, E. et al. Medullary kappa-opioid receptor neurons inhibit pain and itch through a descending circuit. Brain 145, 2586–2601 (2022).

    PubMed  PubMed Central  Google Scholar 

  120. Gao, T. et al. G-Protein-coupled estrogen receptor (GPER) in the rostral ventromedial medulla is essential for mobilizing descending inhibition of itch. J. Neurosci. 41, 7727–7741 (2021).

    PubMed  PubMed Central  CAS  Google Scholar 

  121. Francois, A. et al. A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron 93, 822–839.e6 (2017).

    PubMed  PubMed Central  CAS  Google Scholar 

  122. Kaneko, T. et al. Orexin neurons play contrasting roles in itch and pain neural processing via projecting to the periaqueductal gray. Commun. Biol. 7, 290 (2024).

    PubMed  PubMed Central  Google Scholar 

  123. Kaneko, T. & Kuwaki, T. The opposite roles of orexin neurons in pain and itch neural processing. Peptides 160, 170928 (2023).

    PubMed  CAS  Google Scholar 

  124. Melzack, R. & Wall, P. D. Pain mechanisms: a new theory. Science 150, 971–979 (1965).

    PubMed  CAS  Google Scholar 

  125. Chen, Y. et al. Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors. Proc. Natl Acad. Sci. USA 119, e2118501119 (2022).

    PubMed  PubMed Central  CAS  Google Scholar 

  126. Mantyh, P. W. et al. Inhibition of hyperalgesia by ablation of lamina I spinal neurons expressing the substance P receptor. Science 278, 275–279 (1997).

    PubMed  CAS  Google Scholar 

  127. Davidson, S. & Giesler, G. J. The multiple pathways for itch and their interactions with pain. Trends Neurosci. 33, 550–558 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  128. Bardoni, R. et al. Pain inhibits GRPR neurons via GABAergic signaling in the spinal cord. Sci. Rep. 9, 15804 (2019).

    PubMed  PubMed Central  Google Scholar 

  129. Liu, Y. et al. VGLUT2-dependent glutamate release from nociceptors is required to sense pain and suppress itch. Neuron 68, 543–556 (2010).

    PubMed  PubMed Central  CAS  Google Scholar 

  130. Prajapati, J. N., Shah, D. P. & Barik, A. An intra-brainstem circuitry for pain-induced inhibition of itch. Neuroscience 568, 95–107 (2025).

    PubMed  CAS  Google Scholar 

  131. Yuan, L., Liang, T. Y., Deng, J. & Sun, Y. G. Dynamics and functional role of dopaminergic neurons in the ventral tegmental area during itch processing. J. Neurosci. 38, 9856–9869 (2018).

    PubMed  PubMed Central  CAS  Google Scholar 

  132. Demirtas, S., Houssais, C., Tanniou, J., Misery, L. & Brenaut, E. Effectiveness of a music intervention on pruritus: an open randomized prospective study. J. Eur. Acad. Dermatol. Venereol. 34, 1280–1285 (2020).

    PubMed  CAS  Google Scholar 

  133. Shiratori-Hayashi, M. et al. STAT3-dependent reactive astrogliosis in the spinal dorsal horn underlies chronic itch. Nat. Med. 21, 927–931 (2015).

    PubMed  CAS  Google Scholar 

  134. Hachisuka, J., Chiang, M. C. & Ross, S. E. Itch and neuropathic itch. Pain 159, 603–609 (2018).

    PubMed  PubMed Central  Google Scholar 

  135. Liu, A. W. et al. Scratching promotes allergic inflammation and host defense via neurogenic mast cell activation. Science 387, eadn9390 (2025).

    PubMed  PubMed Central  CAS  Google Scholar 

  136. Flayer, C. H. et al. A gammadelta T cell-IL-3 axis controls allergic responses through sensory neurons. Nature 634, 440–446 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  137. Pavlov, V. A. & Tracey, K. J. The vagus nerve and the inflammatory reflex — linking immunity and metabolism. Nat. Rev. Endocrinol. 8, 743–754 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  138. Yassky, D. & Kim, B. S. Mouse models of itch. J. Investig. Dermatol. 144, 2634–2644 (2024).

    PubMed  Google Scholar 

  139. Kim, J.-I. et al. Human assembloid model of the ascending neural sensory pathway. Nature 642, 143–153 (2025).

    PubMed  PubMed Central  CAS  Google Scholar 

  140. Holle, H., Warne, K., Seth, A. K., Critchley, H. D. & Ward, J. Neural basis of contagious itch and why some people are more prone to it. Proc. Natl Acad. Sci. USA 109, 19816–19821 (2012).

    PubMed  PubMed Central  CAS  Google Scholar 

  141. Schut, C. et al. Brain processing of contagious itch in patients with atopic dermatitis. Front. Psychol. 8, 1267 (2017).

    PubMed  PubMed Central  Google Scholar 

  142. Schut, C., Grossman, S., Gieler, U., Kupfer, J. & Yosipovitch, G. Contagious itch: what we know and what we would like to know. Front. Hum. Neurosci. 9, 57 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  143. Lu, J. S. et al. Contagious itch can be induced in humans but not in rodents. Mol. Brain 12, 38 (2019).

    PubMed  PubMed Central  Google Scholar 

  144. Liljencrantz, J., Pitcher, M. H., Low, L. A., Bauer, L. & Bushnell, M. C. Comment on “Molecular and neural basis of contagious itch behavior in mice”. Science 357, eaan4749 (2017).

    PubMed  PubMed Central  Google Scholar 

  145. Shayan, M. et al. Social interactions and olfactory cues are required for contagious itch in mice. Sci. Rep. 14, 11334 (2024).

    PubMed  PubMed Central  CAS  Google Scholar 

  146. Hsieh, J. C. et al. Urge to scratch represented in the human cerebral cortex during itch. J. Neurophysiol. 72, 3004–3008 (1994).

    PubMed  CAS  Google Scholar 

  147. Leknes, S. G. et al. 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 (2007).

    PubMed  Google Scholar 

  148. Wu, X. B. et al. Excitatory projections from the prefrontal cortex to nucleus accumbens core D1-MSNs and kappa opioid receptor modulate itch-related scratching behaviors. J. Neurosci. 43, 1334–1347 (2023).

    PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The author thanks A. Todd and D. Mu for comments on the manuscript. This work was supported by the National Natural Science Foundation of China (No. 32221003, 32430038), the National Science and Technology Innovation 2030 Major Program (2021ZD0204404), and the New Cornerstone Science Foundation through the Xplorer Prize.

Author information

Authors and Affiliations

  1. Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    Yan-Gang Sun

  2. State Key Laboratory of Brain Cognition and Brain-inspired Intelligence Technology, Shanghai, China

    Yan-Gang Sun

Authors
  1. Yan-Gang Sun
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Yan-Gang Sun.

Ethics declarations

Competing interests

The author declares no competing interests.

Peer review information

Nature Reviews Neuroscience thanks Sarah Ross, Bo Duan and the other, anonymous, reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, YG. Central neural circuits underlying itch sensation. Nat. Rev. Neurosci. 26, 765–777 (2025). https://doi.org/10.1038/s41583-025-00981-8

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41583-025-00981-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing