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

Department of Psychiatry, Washington University in St. Louis, San Luis, Missouri, United States
Nature (Impact Factor: 41.46). 09/2007; 448(7154):700-3. DOI: 10.1038/nature06029
Source: PubMed


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 dermatitis. 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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    • "Apart from brain systems, studies in rodents, cats and non-human primates provide increasing evidence that spinal cord processing is substantially involved in pruriception (Akiyama et al., 2009, 2011; Davidson et al., 2009; Kardon et al., 2014; Moser and Giesler, 2013; Nakano et al., 2008; Nishida et al., 2013; Ross et al., 2010; Sun and Chen, 2007; Yao et al., 1992). One example is the inhibition of superficial dorsal horn neurons through scratching (Akiyama et al., 2011; Davidson et al., 2009). "
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    ABSTRACT: Itch is an independent sensory modality and a very common symptom with manifold causes. However, the neuronal representation of itch perception in the central nervous system is not entirely understood and there is hardly any knowledge about neuronal correlates of itch in the human spinal cord. In the present study we aimed to identify itch-related neural activity in the cervical spinal cord in healthy volunteers employing high-resolution functional magnetic resonance imaging (fMRI). We studied histamine-induced itch on the radial forearm and modulated itch intensity by non-noxious cooling. To control for effects of thermal stimulation (i.e., cooling), volunteers also underwent an identical session without histamine. We studied histamine-induced itch on the radial forearm, by using a block design with alternating blocks of non-noxious cooling separated by blocks of skin temperature. Non-noxious cooling of histamine-treated skin compared to cooling of non-treated skin led to a significant increase in itch perception. On the neural level, itch was paralleled by activation in the dorsal horn of the spinal cord at the transition between spinal segment C5 and C6, ipsilateral to the side of stimulation. These results suggest that itch-related neural activity can be assessed noninvasively in humans at the spinal cord. Copyright © 2014 Elsevier Inc. All rights reserved.
    NeuroImage 12/2014; 108. DOI:10.1016/j.neuroimage.2014.12.019 · 6.36 Impact Factor
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    • "To evaluate the involvement of the central serotonergic system in modulation of itch transmission, we first examined the scratching behavior of Lmx1b f/f/p mice to intradermal injection (i.d.) of chloroquine (CQ), a representative nonhistaminergic pruritogen that acts, in part, via a Mas-related GPCR (MrgprA3) in sensory neurons and GRPR in the spinal cord (Liu et al., 2009; Sun and Chen, 2007). LMX1B is a LIM homeodomain-containing transcription factor that is required for the development of all central 5-HT neurons (Ding et al., 2003). "
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    ABSTRACT: Unlabelled: Central serotonin (5-hydroxytryptophan, 5-HT) modulates somatosensory transduction, but how it achieves sensory modality-specific modulation remains unclear. Here we report that enhancing serotonergic tone via administration of 5-HT potentiates itch sensation, whereas mice lacking 5-HT or serotonergic neurons in the brainstem exhibit markedly reduced scratching behavior. Through pharmacological and behavioral screening, we identified 5-HT1A as a key receptor in facilitating gastrin-releasing peptide (GRP)-dependent scratching behavior. Coactivation of 5-HT1A and GRP receptors (GRPR) greatly potentiates subthreshold, GRP-induced Ca(2+) transients, and action potential firing of GRPR(+) neurons. Immunostaining, biochemical, and biophysical studies suggest that 5-HT1A and GRPR may function as receptor heteromeric complexes. Furthermore, 5-HT1A blockade significantly attenuates, whereas its activation contributes to, long-lasting itch transmission. Thus, our studies demonstrate that the descending 5-HT system facilitates GRP-GRPR signaling via 5-HT1A to augment itch-specific outputs, and a disruption of crosstalk between 5-HT1A and GRPR may be a useful antipruritic strategy. Video abstract:
    Neuron 11/2014; 84(4):821-834. DOI:10.1016/j.neuron.2014.10.003 · 15.05 Impact Factor
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    • "Based on our RNA-Seq results we examined what might account for previous immunostaining reports that describe GRP-containing neurons in DRG [1,2]. Searches for sequences with similar primary structure to the antigen used to produce anti-bombesin/GRP antibodies revealed two candidates that can cross-react, NMB and Substance P. Both of these peptides are present in very high quantities in DRG neurons. "
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    ABSTRACT: Background Three neuropeptides, gastrin releasing peptide (GRP), natriuritic precursor peptide B (NPPB), and neuromedin B (NMB) have been proposed to play roles in itch sensation. However, the tissues in which these peptides are expressed and their positions in the itch circuit has recently become the subject of debate. Here we used next-gen RNA-Seq to examine the expression of transcripts coding for GRP, NPPB, NMB, and other peptides in DRG, trigeminal ganglion, and the spinal cord as well as expression levels for their cognate receptors in these tissues. Results RNA-Seq demonstrates that GRP is not transcribed in mouse, rat, or human sensory ganglia. NPPB, which activates natriuretic peptide receptor 1 (NPR1), is well expressed in mouse DRG and less so in rat and human, whereas NPPA, which also acts on the NPR1 receptor, is expressed in all three species. Analysis of transcripts expressed in the spinal cord of mouse, rat, and human reveals no expression of Nppb, but unambiguously detects expression of Grp and the GRP-receptor (Grpr). The transcripts coding for NMB and tachykinin peptides are among the most highly expressed in DRG. Bioinformatics comparisons using the sequence of the peptides used to produce GRP-antibodies with proteome databases revealed that the C-terminal primary sequence of NMB and Substance P can potentially account for results from previous studies which showed GRP-immunostaining in the DRG. Conclusions RNA-Seq corroborates a primary itch afferent role for NPPB in mouse and potentially NPPB and NPPA in rats and humans, but does not support GRP as a primary itch neurotransmitter in mouse, rat, or humans. As such, our results are at odds with the initial proposal of Sun and Chen (2007) that GRP is expressed in DRG. By contrast, our data strongly support an itch pathway where the itch-inducing actions of GRP are exerted through its release from spinal cord neurons.
    Molecular Pain 08/2014; 10(1):44. DOI:10.1186/1744-8069-10-44 · 3.65 Impact Factor
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