Persistent itch is an aversive condition that results in a severely diminished quality of life. Our approach to address this important health issue is to gain a better understanding of the underlying neural circuits and pathways. Specifically, we propose to investigate the mechanisms through which KOR signaling modulates itch. The long-term goal of our research program is aimed at the development of novel interventions for itch that are both safe and effective. We previously found that mice lacking the transcription factor Bhlhb5 show elevated itch, and that this effect is caused by the loss of a specific population spinal inhibitory interneurons that express the dynorphin. However, the neurons that respond to dynorphin ? those that express KOR ? remained unknown, and the neural circuits through which KOR agonists inhibit itch were unclear. To address these gaps, our lab developed novel tools (KOR-cre allele) and approaches (ex vivo preparation) to study this circuitry. We also discovered that in models of pathological itch there is abnormal bursting behavior in lamina I spinal neurons. Here we propose to elucidate the circuitry through which KOR agonists inhibit itch, combining anatomical (AIM 1), behavioral (AIM 2), physiological (AIM 3), and translational (AIM 4) approaches. Our overall hypothesis is that KOR signaling acts on both primary afferents and spinal neurons to inhibit acute pruritoception, and that KOR agonists will continue to be effective in the presence of persistent itch. Our proposal is innovative because it combines these state-of-the-art tools and approaches to elucidate the neural circuits through which KOR agonists inhibit pruritoception. The combination of conceptual advances and therapeutic insight into the neural circuitry through which KOR agonists inhibit itch makes this proposal highly significant to human health.

Public Health Relevance

Itch is the number one reason for a dermatological visit, and it can severely diminish quality of life. Kappa opioid receptor (KOR) agonists are emerging as a potential treatment, but the underlying neural circuits through which KOR agonists inhibit itch are unclear. Our research will define the cellular mechanism through which KOR agonists inhibit itch.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063772-07
Application #
9664582
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tseng, Hung H
Project Start
2013-02-11
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Hachisuka, Junichi; Omori, Yu; Chiang, Michael C et al. (2018) Wind-up in lamina I spinoparabrachial neurons: a role for reverberatory circuits. Pain 159:1484-1493
Sheahan, Tayler D; Hachisuka, Junichi; Ross, Sarah E (2018) Small RNAs, but Sizable Itch: TRPA1 Activation by an Extracellular MicroRNA. Neuron 99:421-422
Snyder, Lindsey M; Chiang, Michael C; Loeza-Alcocer, Emanuel et al. (2018) Kappa Opioid Receptor Distribution and Function in Primary Afferents. Neuron 99:1274-1288.e6
Hachisuka, Junichi; Chiang, Michael C; Ross, Sarah E (2018) Itch and neuropathic itch. Pain 159:603-609
Hachisuka, Junichi; Baumbauer, Kyle M; Omori, Yu et al. (2016) Semi-intact ex vivo approach to investigate spinal somatosensory circuits. Elife 5:
Snyder, Lindsey M; Kuzirian, Marissa S; Ross, Sarah E (2016) An Unexpected Role for TRPV4 in Serotonin-Mediated Itch. J Invest Dermatol 136:7-9
Huang, Huizhen; Kuzirian, Marissa S; Cai, Xiaoyun et al. (2016) Generation of a NK1R-CreER knockin mouse strain to study cells involved in Neurokinin 1 Receptor signaling. Genesis 54:593-601
Cai, Xiaoyun; Kardon, Adam P; Snyder, Lindsey M et al. (2016) Bhlhb5::flpo allele uncovers a requirement for Bhlhb5 for the development of the dorsal cochlear nucleus. Dev Biol 414:149-60
Saloman, Jami L; Scheff, Nicole N; Snyder, Lindsey M et al. (2016) Gi-DREADD Expression in Peripheral Nerves Produces Ligand-Dependent Analgesia, as well as Ligand-Independent Functional Changes in Sensory Neurons. J Neurosci 36:10769-10781
Cai, Xiaoyun; Huang, Huizhen; Kuzirian, Marissa S et al. (2016) Generation of a KOR-Cre knockin mouse strain to study cells involved in kappa opioid signaling. Genesis 54:29-37

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