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A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord


Itching, or pruritus, is defined as an unpleasant cutaneous sensation that serves as a physiological self-protective mechanism to prevent the body from being hurt by harmful external agents. Chronic itch represents a significant clinical problem resulting from renal diseases and liver diseases, as well as several serious skin diseases such as atopic dermatitis1,2,3. The identity of the itch-specific mediator in the central nervous system, however, remains elusive. Here we describe that the gastrin-releasing peptide receptor (GRPR) plays an important part in mediating itch sensation in the dorsal spinal cord. We found that gastrin-releasing peptide is specifically expressed in a small subset of peptidergic dorsal root ganglion neurons, whereas expression of its receptor GRPR is restricted to lamina I of the dorsal spinal cord. GRPR mutant mice showed comparable thermal, mechanical, inflammatory and neuropathic pain responses relative to wild-type mice. In contrast, induction of scratching behaviour was significantly reduced in GRPR mutant mice in response to pruritogenic stimuli, whereas normal responses were evoked by painful stimuli. Moreover, direct spinal cerebrospinal fluid injection of a GRPR antagonist significantly inhibited scratching behaviour in three independent itch models. These data demonstrate that GRPR is required for mediating the itch sensation rather than pain, at the spinal level. Our results thus indicate that GRPR may represent the first molecule that is dedicated to mediating the itch sensation in the dorsal horn of the spinal cord, and thus may provide a central therapeutic target for antipruritic drug development.

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Figure 1: Expression pattern of GRP and GRPR in adult DRG and dorsal horn of the spinal cord.
Figure 2: Pain behaviours and locomotor activity are normal in GRPR mutant mice.
Figure 3: Scratching behaviour is reduced in GRPR mutant mice.
Figure 4: Effects of GRPR agonist and antagonist on scratching behaviour.


  1. 1

    Paus, R., Schmelz, M., Biro, T. & Steinhoff, M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J. Clin. Invest. 116, 1174–1186 (2006)

    CAS  Article  Google Scholar 

  2. 2

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

    CAS  Article  Google Scholar 

  3. 3

    Greaves, M. W. Itch in systemic disease: therapeutic options. Dermatol. Ther. 18, 323–327 (2005)

    Article  Google Scholar 

  4. 4

    Roesler, R., Henriques, J. A. & Schwartsmann, G. Gastrin-releasing peptide receptor as a molecular target for psychiatric and neurological disorders. CNS Neurol. Disord. Drug Targets 5, 197–204 (2006)

    CAS  Article  Google Scholar 

  5. 5

    Battey, J. & Wada, E. Two distinct receptor subtypes for mammalian bombesin-like peptides. Trends Neurosci. 14, 524–528 (1991)

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Gmerek, D. E. & Cowan, A. Studies on bombesin-induced grooming in rats. Peptides 4, 907–913 (1983)

    CAS  Article  Google Scholar 

  8. 8

    Gmerek, D. E. & Cowan, A. Bombesin—a central mediator of pruritus? Br. J. Dermatol. 109, 239 (1983)

    CAS  Article  Google Scholar 

  9. 9

    O'Donohue, T. L. et al. A role for bombesin in sensory processing in the spinal cord. J. Neurosci. 4, 2956–2962 (1984)

    CAS  Article  Google Scholar 

  10. 10

    Moody, T. W. & Merali, Z. Bombesin-like peptides and associated receptors within the brain: distribution and behavioral implications. Peptides 25, 511–520 (2004)

    CAS  Article  Google Scholar 

  11. 11

    Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H. O. & Torebjork, H. E. Specific C-receptors for itch in human skin. J. Neurosci. 17, 8003–8008 (1997)

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    Kuraishi, Y., Nagasawa, T., Hayashi, K. & Satoh, M. Scratching behavior induced by pruritogenic but not algesiogenic agents in mice. Eur. J. Pharmacol. 275, 229–233 (1995)

    CAS  Article  Google Scholar 

  14. 14

    Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. Molecular cloning of a potential proteinase activated receptor. Proc. Natl Acad. Sci. USA 91, 9208–9212 (1994)

    ADS  CAS  Article  Google Scholar 

  15. 15

    Steinhoff, M. et al. Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism. Nature Med. 6, 151–158 (2000)

    CAS  Article  Google Scholar 

  16. 16

    Steinhoff, M. et al. Proteinase-activated receptor-2 mediates itch: a novel pathway for pruritus in human skin. J. Neurosci. 23, 6176–6180 (2003)

    CAS  Article  Google Scholar 

  17. 17

    Shimada, S. G., Shimada, K. A. & Collins, J. G. Scratching behavior in mice induced by the proteinase-activated receptor-2 agonist, SLIGRL-NH2. Eur. J. Pharmacol. 530, 281–283 (2006)

    CAS  Article  Google Scholar 

  18. 18

    Inan, S. & Cowan, A. Kappa opioid agonists suppress chloroquine-induced scratching in mice. Eur. J. Pharmacol. 502, 233–237 (2004)

    CAS  Article  Google Scholar 

  19. 19

    Green, A. D., Young, K. K., Lehto, S. G., Smith, S. B. & Mogil, J. S. Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain 124, 50–58 (2006)

    CAS  Article  Google Scholar 

  20. 20

    Ladenheim, E. E., Taylor, J. E., Coy, D. H., Moore, K. A. & Moran, T. H. Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP. Am. J. Physiol. 271, R180–R184 (1996)

    CAS  PubMed  Google Scholar 

  21. 21

    Wang, L. H. et al. des-Met carboxyl-terminally modified analogues of bombesin function as potent bombesin receptor antagonists, partial agonists, or agonists. J. Biol. Chem. 265, 15695–15703 (1990)

    CAS  PubMed  Google Scholar 

  22. 22

    Stander, S. & Schmelz, M. Chronic itch and pain—similarities and differences. Eur. J. Pain 10, 473–478 (2006)

    Article  Google Scholar 

  23. 23

    McMahon, S. B. & Koltzenburg, M. Itching for an explanation. Trends Neurosci. 15, 497–501 (1992)

    CAS  Article  Google Scholar 

  24. 24

    Shumyatsky, G. P. et al. Identification of a signaling network in lateral nucleus of amygdala important for inhibiting memory specifically related to learned fear. Cell 111, 905–918 (2002)

    CAS  Article  Google Scholar 

  25. 25

    Kroog, G. S., Jensen, R. T. & Battey, J. F. Mammalian bombesin receptors. Med. Res. Rev. 15, 389–417 (1995)

    CAS  Article  Google Scholar 

  26. 26

    Sowunmi, A., Walker, O. & Salako, L. A. Pruritus and antimalarial drugs in Africans. Lancet 2, 213 (1989)

    CAS  Article  Google Scholar 

  27. 27

    Hampton, L. L. et al. Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice. Proc. Natl Acad. Sci. USA 95, 3188–3192 (1998)

    ADS  CAS  Article  Google Scholar 

  28. 28

    Chen, Z. F. et al. The paired homeodomain protein DRG11 is required for the projection of cutaneous sensory afferent fibers to the dorsal spinal cord. Neuron 31, 59–73 (2001)

    CAS  Article  Google Scholar 

  29. 29

    Wozniak, D. F. et al. Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults. Neurobiol. Dis. 17, 403–414 (2004)

    CAS  Article  Google Scholar 

  30. 30

    Hylden, J. L. & Wilcox, G. L. Intrathecal morphine in mice: a new technique. Eur. J. Pharmacol. 67, 313–316 (1980)

    CAS  Article  Google Scholar 

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We thank J. Yin, C.-S. Qiu and K.-H. Zhang for technical assistance and J. Battey for providing GRPR mutant mice. We are grateful to A. Basbaum, E. Carstens, L. Hampton and J. Battey for critical comments on the manuscript. We also thank D. H. Coy for providing the GRPR antagonist. The work was supported by an NIH RO1 to Z.F.C.

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Correspondence to Zhou-Feng Chen.

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

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