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

Abstract

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.

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Acknowledgements

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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This file contains Supplementary Methods, Supplementary Figures 1-7 with Legends and additional references. (PDF 710 kb)

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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). https://doi.org/10.1038/nature06029

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