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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    • "In addition, an increased level of serum BNP was found to be associated with the degree of pruritus in hemodialysis patients (Shimizu et al., 2014). Anatomic and pharmacological studies have demonstrated that GRP-GRPR system acts downstream of the BNP-NPRA signaling in the pruriceptive circuit as an itchselective regulation by BNP (Mishra and Hoon, 2013). However , a series of experiments conducted later indicated that BNP is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway (Liu et al., 2014). "
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    ABSTRACT: B-type natriuretic peptide (BNP)-Natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomical evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. Our results showed that Intrathecal administration of BNP (0.3-3 nmol) dose-dependently elicited scratching responses, which can be blocked by a NPRA antagonist A71915. However, A71915 had no effect on intrathecal GRP-induced scratching. In contrast, pretreatment with a GRPR antagonist RC-3095 inhibited BNP-induced scratching. Immunostaining revealed that NPRA proteins colocalize with GRP, but not GRPR, in the superficial area of dorsal horn, whereas BNP proteins do not colocalize with either GRP or GRPR in the dorsal horn. Intradermal administration of ligands including endothelin-1, U-46619, BAM8-22, and SLIGRL, increased scratching bouts at different levels of magnitude. Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch.
    Preview · Article · Dec 2015 · Journal of Pharmacology and Experimental Therapeutics
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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. "

    Full-text · Dataset · Jul 2015
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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.
    Full-text · Article · Aug 2014 · International Journal of Nephrology and Renovascular Disease
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