The neural basis of Itch is poorly understood despite its importance as a primary quality of cutaneous sensation and as a clinical symptom of many neurological and other disorders. During our previous funding period we discovered that itch is mediated by subpopulations of nociceptive primary neurons and nociceptive spinothalamic tract (STT) neurons, some responsive to histamine, and others to the spicules of cowhage that evoked a histamine independent itch via a novel cysteine protease that we identified. We devised a precise method of eliciting pruritic and nociceptive chemically evoked sensations (dysesthesias) by using chemically inert (heat inactivated) spicules soaked in an endogenous cysteine protease, histamine, or capsaicin. We propose to continue our combined, psychophysical and neurophysiological study of itch requiring the integrated efforts of three different projects each using a different experimental approach. Project 1 will measure psychophysically the itch, nociceptive sensations and dysesthesias evoked by heat-inactivated cowhage spicules containing histamine, capsaicin or an endogenous cysteine protease. The effects of mechanical, thermal or chemical stimuli in enhancing or suppressing itch and the effects of blocking conduction in myelinated nerve fibers will be examined to reveal underlying neural mechanisms controlling itch. Project 2 will electrophysiologically record the responses, to the same stimuli used in project 1, of peripheral nerve fibers in monkey to determine the separate contributions of nociceptive neurons with myelinated vs. non-myelinated axons to itch and nociceptive sensations and to the enhancement and inhibition of itch. Project 3 will electrophysiologically record the responses of STT- and thalamic neurons to the same stimuli used in projects 1 &2. In addition, the effects of iontophoretic application of morphine, a GABA inhibitor, and the blocking of descending pathways from suprasegmental areas on STT neuronal responses will reveal spinal mechanisms of the enhancement and inhibition of itch, nociception and pruritic dysesthesias. A core providing administration, instrumentation, statistics and informatics will facilitate the collection, analysis and evaluation of the data obtained from each project. By increasing our understanding of the peripheral and central neural mechanisms that code and modulate itch and nociceptive sensations, our combined studies will provide new targets for novel therapies to relieve itch and pain.

Public Health Relevance

The proposed psychophysical and neurophysiological studies of experimentally produced itch and pain will advance our understanding of how these sensations are mediated by sensory neurons in the peripheral and central nervous system. Identification of these neurons and their properties will provide targets for pharmacological therapies to relieve chronic itch and pain in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS047399-09
Application #
8288122
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Gnadt, James W
Project Start
2003-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,192,197
Indirect Cost
$283,466
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Wang, Tao; Hurwitz, Olivia; Shimada, Steven G et al. (2015) Chronic Compression of the Dorsal Root Ganglion Enhances Mechanically Evoked Pain Behavior and the Activity of Cutaneous Nociceptors in Mice. PLoS One 10:e0137512
Qu, Lintao; Fu, Kai; Yang, Jennifer et al. (2015) CXCR3 chemokine receptor signaling mediates itch in experimental allergic contact dermatitis. Pain 156:1737-46
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Jansen, Nico A; Giesler Jr, Glenn J (2015) Response characteristics of pruriceptive and nociceptive trigeminoparabrachial tract neurons in the rat. J Neurophysiol 113:58-70
Qu, Lintao; Fan, Ni; Ma, Chao et al. (2014) Enhanced excitability of MRGPRA3- and MRGPRD-positive nociceptors in a model of inflammatory itch and pain. Brain 137:1039-50
LaMotte, Robert H; Dong, Xinzhong; Ringkamp, Matthias (2014) Sensory neurons and circuits mediating itch. Nat Rev Neurosci 15:19-31
Wooten, Matthew; Weng, Hao-Jui; Hartke, Timothy V et al. (2014) Three functionally distinct classes of C-fibre nociceptors in primates. Nat Commun 5:4122

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