Abstract

Chronic itch is a presenting sign in numerous diseases associated with the skin, immune and nervous systems. Chronic itch is largely resistant to conventional antihistamines, and few effective therapies are available. In order to develop novel therapeutics against chronic itch, there is a pressing need for identification of itc-specific signaling mechanisms involved. Activation of kappa opioid receptor (KOR) can inhibit chronic itch. However, KOR activation is associated with several side effects that might have hindered its use as therapeutics. We recently found that gastrin-releasing peptide receptor (GRPR) is an important receptor for the development of chronic itch, and KOR activation attenuates itch by inhibiting GRPR function.
Aim 1 is to determine whether KOR inhibits itch by a blockade of GRPR function.
Aim 2 is to examine the role of PKC in KOR activation-mediated inhibition.
Aim 3 is to determine whether KOR activation inhibits itch via KOR-GRPR heteromerization. The proposed studies are highly translational because it will provide mechanistic insights into KOR-mediated inhibition of chronic itch and will significantly expand the pool of the targets that may be explored for future KOR-GRPR-based anti-pruritus drug discovery program.

Public Health Relevance

Chronic itch is a major unmet medical problem which remains poorly understood. We will examine signaling molecules that are necessary for mediating kappa opioid receptor activation-mediated inhibition of chronic itch. Our proposed studies will discover potential drug targets and may provide a basis for designing a better strategy for chronic itch management.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS094344-02
Application #
9128732
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Gnadt, James W
Project Start
2015-09-01
Project End
2020-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Munanairi, Admire; Liu, Xian-Yu; Barry, Devin M et al. (2018) Non-canonical Opioid Signaling Inhibits Itch Transmission in the Spinal Cord of Mice. Cell Rep 23:866-877
Barry, Devin M; Munanairi, Admire; Chen, Zhou-Feng (2018) Spinal Mechanisms of Itch Transmission. Neurosci Bull 34:156-164
Wan, Li; Jin, Hua; Liu, Xian-Yu et al. (2017) Distinct roles of NMB and GRP in itch transmission. Sci Rep 7:15466
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