Itch is an unpleasant sensation associated with the desire to scratch. While acute itch commonly occurs with insect bites, allergic reactions or contact with certain plants, chronic itch is a common symptom of many dermatological conditions and systemic disease. Chronic itch is poorly-treated, negatively impacts the quality of life, and carries a heavy economic and social burden. There is a great need to better understand mechanisms of itch to develop more effective treatments. This proposal will use behavioral assessment of scratching, combined with electrophysiological and neuroanatomical approaches, to investigate mechanisms of itch transmission in normal animals and in animal models of chronic itch. The project consists of 5 Specific Aims.
Specific Aim 1 will investigate if intradermal (id) microinjection of the itch mediators serotonin, agonists of protease-activated receptor (PAR) subtypes 2 and 4, and histamine, elicit scratching behavior in mice in a manner that is consistent with itch sensation in humans. We will test if scratching is reduced by ?-opioid antagonists but not by morphine, which often evokes itch.
Specific Aim 2 seeks to identify the locations and functional properties of pruritogen-activated neurons in the superficial dorsal horn of the mouse. This will be accomplished using a neuroanatomical approach to localize pruritogen-sensitive neurons, and an electrophysiological approach to record the responses of neurons in these locations to pruritic and noxious stimulation of the skin in anesthetized mice. We hypothesize that a sub-population of neurons in superficial laminae of the murine lumbar dorsal horn responds to id pruritogens in a manner consistent with a role in signaling acute itch.
Specific Aim 3 will investigate the role of the spinothalamic and spinoparabrachial pathways in mediating itch in mice and rats using a neuroanatomical double-label strategy.
Specific Aim 4 will investigate a role for substance P and other neuropeptides in spinal itch transmission, using neurotoxic ablation of neurons expressing the NK-1 receptor as well as intracisternal delivery of antagonists.
Specific Aim 5 will investigate sensitization of itch-signaling pathways in mouse models of chronic itch. We hypothesize that experimental chronic itch will lead to enhanced scratching elicited by pruritogens and also algogens such as capsaicin. We further hypothesize that experimental chronic itch sensitizes superficial dorsal horn neurons, manifested by increased Fos expression and functional hyperexcitability as exhibited by abnormal spontaneous activity and increased responses to pruritogens. These hypotheses will be addressed using two murine models of chronic itch, the NC """"""""itchy"""""""" mouse strain, and experimental dry skin.

Public Health Relevance

Chronic itch is a common symptom of many dermatological conditions and systemic diseases. The itch is poorly-treated and carries a heavy economic and social burden, creating a great need to better understand mechanisms of itch to develop more effective treatments. This proposal will use behavioral assessment of scratching, combined with electrophysiological and neuroanatomical approaches, to investigate mechanisms of itch transmission in normal animals and how itch transmission is altered in animal models of chronic itch.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR057194-03
Application #
8099665
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Tseng, Hung H
Project Start
2009-07-10
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$328,334
Indirect Cost
Name
University of California Davis
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Akiyama, T; Nagamine, M; Davoodi, A et al. (2017) Innocuous warming enhances peripheral serotonergic itch signaling and evokes enhanced responses in serotonin-responsive dorsal horn neurons in the mouse. J Neurophysiol 117:251-259
Carstens, E (2016) Many parallels between itch and pain research. Eur J Pain 20:5-7
Akiyama, Tasuku; Ivanov, Margaret; Nagamine, Masaki et al. (2016) Involvement of TRPV4 in Serotonin-Evoked Scratching. J Invest Dermatol 136:154-60
Akiyama, Tasuku; Curtis, Eric; Nguyen, Tony et al. (2016) Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice. J Comp Neurol 524:244-56
Carstens, Earl; Akiyama, Tasuku (2016) Central Mechanisms of Itch. Curr Probl Dermatol 50:11-7
Akiyama, Tasuku; Lerner, Ethan A; Carstens, E (2015) Protease-activated receptors and itch. Handb Exp Pharmacol 226:219-35
Klein, A H; Trannyguen, Minh; Joe, Christopher L et al. (2015) Thermosensitive transient receptor potential (TRP) channel agonists and their role in mechanical, thermal and nociceptive sensations as assessed using animal models. Chemosens Percept 8:96-108
Akiyama, Tasuku; Nguyen, Tony; Curtis, Eric et al. (2015) A central role for spinal dorsal horn neurons that express neurokinin-1 receptors in chronic itch. Pain 156:1240-6
Akiyama, Tasuku; Ivanov, Margaret; Nagamine, Masaki et al. (2015) Involvement of TRPV4 in serotonin-evoked scratching. J Invest Dermatol :
Akiyama, T; Nagamine, M; Davoodi, A et al. (2015) Intradermal endothelin-1 excites bombesin-responsive superficial dorsal horn neurons in the mouse. J Neurophysiol 114:2528-34

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