The Cells and Circuitry for Itch Responses in Mice

Molecular Genetics Unit, Laboratory of Sensory Biology, National Institute of Dental and Craniofacial Research (NIDCR), NIH, Building 49, Room 1A16, 49 Convent Drive, Bethesda, MD 20892, USA.
Science (Impact Factor: 33.61). 05/2013; 340(6135):968-971. DOI: 10.1126/science.1233765
Source: PubMed


Itch is triggered by somatosensory neurons expressing the ion channel TRPV1 (transient receptor potential cation channel subfamily V member 1), but the mechanisms underlying this nociceptive response remain poorly understood. Here, we show that the neuropeptide natriuretic polypeptide b (Nppb) is expressed in a subset of TRPV1 neurons and found that Nppb(-/-) mice selectively lose almost all behavioral responses to itch-inducing agents. Nppb triggered potent scratching when injected intrathecally in wild-type and Nppb(-/-) mice, showing that this neuropeptide evokes itch when released from somatosensory neurons. Itch responses were blocked by toxin-mediated ablation of Nppb-receptor-expressing cells, but a second neuropeptide, gastrin-releasing peptide, still induced strong responses in the toxin-treated animals. Thus, our results define the primary pruriceptive neurons, characterize Nppb as an itch-selective neuropeptide, and reveal the next two stages of this dedicated neuronal pathway.

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Available from: Santosh K Mishra, Sep 12, 2014
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    • "Dorsal horn excitatory and inhibitory neurons are extremely heterogeneous, as indicated by distinct molecular markers, firing patterns, and morphologies (Ribeiro-da-Silva and De Koninck, 2008; Todd, 2010). One effective way to identify the spinal neurons required to process somatic sensory information has been the use of saporin-conjugated peptides to ablate spinal neurons expressing specific peptide receptors (Carstens et al., 2010; Mantyh et al., 1997 ; Mishra and Hoon, 2013; Sun et al., 2009). However, this approach has a potential complication, which is that intrathecal injection of a saporin-conjugated peptide might ablate central terminals originating from primary sensory neurons that also express the receptor for this particular peptide. "

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    • "It has been reported that BNP is a neuropeptide in pruriceptive neurons.11 Mice intrathecally given BNP showed a scratch response.11 "
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    ABSTRACT: Introduction and objective While pruritus is a common complication in hemodialysis patients, the pathophysiological mechanisms remain obscure. Recently, B-type (brain) natriuretic peptide (BNP) has been defined as an itch-selective neuropeptide in pruriceptive neurons in mice, and higher serum levels of BNP are frequently observed in hemodialysis patients. The objective of the present study was to evaluate the role of serum BNP in pruritus in patients undergoing hemodialysis. Patients and methods The current cross-sectional study was performed on 43 patients undergoing maintenance hemodialysis. A visual analog scale (VAS) measuring the general severity of pruritus (values from 0 to 10, with higher values indicating more severe pruritus) in daytime and at night was self-reported by patients. Each patient’s background and laboratory tests, including serum BNP in the post-hemodialysis period, were collected. The correlation between VAS and clinical parameters was evaluated. Results Both daytime and nighttime VAS scores in diabetic patients were significantly less than those in nondiabetic patients. Multiple regression analysis revealed that pruritus in daytime was worsened by serum BNP (β=2.0, t=2.4, P=0.03), calcium (β=4.4, t=5.2, P<0.0001), and β2-microglobulin (β=2.0, t=3.0, P=0.007), while it was eased by age (β=−2.2, t=−3.2, P=0.0004). Nocturnal pruritus was severe in nondiabetic patients (β=1.7, t=3.8, P=0.0005) and weakened by the total iron binding capacity (β=−2.9, t=−3.1, P=0.004). Conclusion It is suggested that a higher level of serum BNP increases the pruritus of hemodialysis patients in daytime and that diabetic patients are less sensitive to itch, especially at nighttime.
    International Journal of Nephrology and Renovascular Disease 08/2014; 7:329-35. DOI:10.2147/IJNRD.S65929
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    • "In contrast, Nppb was virtually absent in non-TRPV1-neurons whereas Tac1 and Nmb showed some overlap. NMB, Substance P and NPPB have been implicated as mediators of nociceptive processes [4,7,12]. The itch-specific neurotransmitter NPPB has two other paralogs NPPA and NPPC. "
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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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