The long-term objective of this proposal is to study the molecular mechanisms that underlie itch sensation at the spinal level. Although acute itch serves as a defense mechanism, chronic itch or pruritus represents a significant clinical problem for which no effective drugs are available. The dorsal spinal cord neurons are essential in processing, integrating and relaying itch information from the periphery to the brain. The molecular mechanisms underlying itch sensation in the spinal cord, however, are not well understood. We have recently shown that gastrin-releasing peptide receptor (GRPR), a mammalian homologue of bombesin-like peptide receptor family, has an important role in mediating itch sensation in the spinal cord. In contrast, GRPR is not required for pain sensation. GRPR thus is the first itch-specific molecule identified in the central nervous system. Recently, we also found that neuromedin B receptor (NMBR), the second mammalian bombesin-like peptide receptor, may also play a role in mediating itch sensation. In this proposal, we would like to study the roles of GRPR and NMBR in the transmission of itch and pain signals.
In aim 1, we will test the hypothesis that NMBR has a role in mediating itch sensation in the spinal cord, and determine whether NMBR and GRPR have redundant function in this aspect. Both pharmacological and genetic approaches will be used to test this hypothesis.
Aim 2 will determine whether NMBR is required for pain sensation and whether NMBR and GRPR may have redundant functions in pain by examining pain behaviors of NMBR mutant and NMBR/GRPR double mutant mice and by pharmacological studies.
Aim 3 will test the hypothesis that spinal morphine-induced pruritus is dependent on the GRPR/NMBR signaling pathways.
In aim 4, we will examine the roles of GRPR/NMBR+ cells in itch sensation by ablating GRPR/NMBR+ cells in the spinal cord followed by behavioral experiments. The proposed studies should not only delineate the roles of GRPR and NMBR but also of neurons expressing these receptors in itch sensation in the spinal cord. Together, our studies will unravel the central mechanisms underlying itch sensation and pave the way for designing new therapeutic strategy to treat chronic pruritus.

Public Health Relevance

Chronic itch is a serious clinical health problem which is difficult to treat. We will study the roles of GRPR and NMBR, two mammalian bombesin-related receptors, and neurons expressing these receptors in the itch sensation in the spinal cord. Our proposed studies will lead to a better understanding of the itch pathway and pave the way for better designing the strategy for the treatment of chronic itch.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056318-05
Application #
8453255
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Tseng, Hung H
Project Start
2009-04-03
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$308,785
Indirect Cost
$105,637
Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhao, Zhong-Qiu; Liu, Xian-Yu; Jeffry, Joseph et al. (2014) Descending control of itch transmission by the serotonergic system via 5-HT1A-facilitated GRP-GRPR signaling. Neuron 84:821-34
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 81:1360-74
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
Jeffry, Joseph; Kim, Seungil; Chen, Zhou-Feng (2011) Itch signaling in the nervous system. Physiology (Bethesda) 26:286-92
Liu, Qin; Tang, Zongxiang; Surdenikova, Lenka et al. (2009) Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell 139:1353-65
Sun, Yan-Gang; Zhao, Zhong-Qiu; Meng, Xiu-Li et al. (2009) Cellular basis of itch sensation. Science 325:1531-4