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.
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.
|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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