Chronic itch is a presenting sign in numerous diseases associated with the skin, the immune, and the nervous systems. Chronic itch is largely resistant to conventional antihistamines, and few effective therapies are available. We have previously uncovered a small subset of itch- specific neurons which express gastrin-releasing peptide receptor (GRPR), an itch receptor, in the spinal cord. GRPR+ neurons are required for pruritoceptive but not for nociceptive transmission. We have also begun to elucidate the function of neuromedin B receptor (NMBR), another itch receptor in the spinal cord. Our goal is to investigate fundamental mechanisms of itch transmission. We will take advantage of several unique mouse lines to examine the dorsal horn itch circuitry at the single cell level.
Aim 1 will determine neurochemical, anatomic and electrophysiological properties of GRPR neurons. We will examine the neurotransmitter phenotype of GRPR neurons and whether GRPR neurons are projection or interneurons by retrograde labeling. We will also examine electrophysiological properties of GRPR neurons using whole cell patch-clamp recording.
Aim 2 will determine the synaptic mechanisms underlying GRP-mediated itch transmission. We will test the hypothesis that GRP-evoked excitation of GRPR neurons is mediated by modulation of ionotropic glutamate receptors (iGluRs) and GRP-dependent mechanism is differentially involved in pruritogens-induced pruriceptive transmission. We will also determine the role of glutamatergic input in this process and examine whether nonhistaminergic and histaminergic pruritogen act through GRP and iGluRs.
Aim 3 will determine molecular properties and function of itch-sensing neurons in chronic itch condition. We will determine whether ectopic GRPR expression induced in chronic itch condition is dependent on primary GRPR neurons by cell ablation approach. Moreover, we will characterize the electric properties of GRPR neurons in chronic itch condition. Finally, we will examine the role of NMBR neurons in itch sensation using NMB-saporin approach.

Public Health Relevance

Chronic itch is a major unmet medical problem which remains poorly understood. We will study the signaling mechanism in the spinal cord using a wide range of approaches. Our proposed studies will lead to a better understanding of central neural mechanism that underlies the modulation of itch transmission, and may provide a basis for designing a better strategy for chronic itch management.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR056318-06
Application #
8631526
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Tseng, Hung H
Project Start
2008-07-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
6
Fiscal Year
2014
Total Cost
$467,959
Indirect Cost
$153,287
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Wan, Li; Jin, Hua; Liu, Xian-Yu et al. (2017) Distinct roles of NMB and GRP in itch transmission. Sci Rep 7:15466
Barry, Devin M; Yu, Yao-Qing; Hao, Yan et al. (2017) Response to Comment on ""Molecular and neural basis of contagious itch behavior in mice"". Science 357:
Yu, Yao-Qing; Barry, Devin M; Hao, Yan et al. (2017) Molecular and neural basis of contagious itch behavior in mice. Science 355:1072-1076
Barry, Devin M; Munanairi, Admire; Chen, Zhou-Feng (2017) Spinal Mechanisms of Itch Transmission. Neurosci Bull :
Barry, Devin M; Li, Hui; Liu, Xian-Yu et al. (2016) Critical evaluation of the expression of gastrin-releasing peptide in dorsal root ganglia and spinal cord. Mol Pain 12:
Kim, Seungil; Barry, Devin M; Liu, Xian-Yu et al. (2016) Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations. Sci Signal 9:ra71
Zhao, Zhong-Qiu; Wan, Li; Liu, Xian-Yu et al. (2014) Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission. J Neurosci 34:12402-14
Liu, Zhixiang; Zhou, Jingfeng; Li, Yi et al. (2014) Dorsal raphe neurons signal reward through 5-HT and glutamate. Neuron 81:1360-1374
Kim, Ji-Young; Kim, Ana; Zhao, Zhong-Qiu et al. (2014) Postnatal maintenance of the 5-Ht1a-Pet1 autoregulatory loop by serotonin in the raphe nuclei of the brainstem. Mol Brain 7:48
Liu, Xian-Yu; Wan, Li; Huo, Fu-Quan et al. (2014) B-type natriuretic peptide is neither itch-specific nor functions upstream of the GRP-GRPR signaling pathway. Mol Pain 10:4

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