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.
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.
|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:|
|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|
|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|
|Zhao, Zhong-Qiu; Huo, Fu-Quan; Jeffry, Joseph et al. (2013) Chronic itch development in sensory neurons requires BRAF signaling pathways. J Clin Invest 123:4769-80|
|Nattkemper, Leigh A; Zhao, Zhong-Qiu; Nichols, Anna J et al. (2013) Overexpression of the gastrin-releasing peptide in cutaneous nerve fibers and its receptor in the spinal cord in primates with chronic itch. J Invest Dermatol 133:2489-92|
|Liu, Yan; Jiang, Yun'ai; Si, Yunxia et al. (2011) Molecular regulation of sexual preference revealed by genetic studies of 5-HT in the brains of male mice. Nature 472:95-9|
|Liu, Xian-Yu; Liu, Zhong-Chun; Sun, Yan-Gang et al. (2011) Unidirectional cross-activation of GRPR by MOR1D uncouples itch and analgesia induced by opioids. Cell 147:447-58|
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