Chronic itch (puritis) is a severe condition that results in severely diminished quality of life. Moreover, this condition is much more widespread than generally appreciated, representing the most common reason to visit a dermatologist, despite the fact that treatments are generally ineffective. However, while itch is initiated in the skin, i is more than just a skin condition. Rather, itch is a complex and poorly understood sensation that is mediated by neural circuits in the periphery, the spinal cord and the brain. Thus, the long-term goal of our research is to gain a better understanding of the neural circuits that mediate itch wit the view of developing more effective therapies for puritis. We previously discovered that the transcription factor Bhlhb5 is required for the survival of a subset of inhibitory interneurons in he spinal cord (which are here termed B5-I neurons) that are required for normal itch sensation;mice lacking these spinal interneurons suffer from persistent pathological itch. Since B5-I neurons are the first component of an itch circuit to be labeled genetically, studying these neurons provides us with a unique opportunity to unravel the neural basis of itch. Importantly, we have recently discovered that B5-I neurons are a specific subset of spinal interneurons that express dynorphin. This finding is important because dynorphin is a kappa opioid receptor (KOR) agonist, and KOR agonists have recently been shown to relieve itch in rodents and man. We therefore hypothesize that B5-I neurons function to inhibit itch, and that they do so in part through the release of dynorphin in the spinal cord. Here we propose to test this hypothesis in through 3 specific aims:
Aim 1 : Determine the degree to which B5-I neurons are specific to the regulation of itch.
Aim 2 : Dissect neural circuits in the dorsal horn using B5-I neurons as a molecular handle.
Aim 3 : Define the role of spinal dynorphin in itch. Results from these experiments are likely to have major clinical implications for people that suffer from chronic itch because our findings will define a key cellular target for the development of future anti-itch therapies and they will provide important insight into the mechanism of KOR-mediated inhibition of itch.
Chronic itch (puritis) is a common condition that is associated with severely diminished quality of life. Our previous studies have identified a neural subtype in the spinal cord that releases dynorphin and functions to inhibit itch. This proposal will uncover how these neurons inhibit itch and test whether dynorphin plays a key role in this process, thereby providing important mechanistic insight to puritis, which may lead to the development of more effective therapies.
|Elliott, Peter; G'Sell, Max; Snyder, Lindsey M et al. (2017) Automated acoustic detection of mouse scratching. PLoS One 12:e0179662|
|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|
|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|
|Baumbauer, Kyle M; DeBerry, Jennifer J; Adelman, Peter C et al. (2015) Keratinocytes can modulate and directly initiate nociceptive responses. Elife 4:|
|Jung, Cynthia C; Atan, Denize; Ng, David et al. (2015) Transcription factor PRDM8 is required for rod bipolar and type 2 OFF-cone bipolar cell survival and amacrine subtype identity. Proc Natl Acad Sci U S A 112:E3010-9|
|Kardon, Adam P; Polgár, Erika; Hachisuka, Junichi et al. (2014) Dynorphin acts as a neuromodulator to inhibit itch in the dorsal horn of the spinal cord. Neuron 82:573-86|
|Duan, Bo; Cheng, Longzhen; Bourane, Steeve et al. (2014) Identification of spinal circuits transmitting and gating mechanical pain. Cell 159:1417-1432|
Showing the most recent 10 out of 13 publications