Chemical activation of nociceptive neurons may contribute to chronic itch and pain in many disorders of the nervous system. During the last funding period, we determined that cowhage produces itch by a non? histaminergic mechanism, and we identified the pruritic agent in cowhage to be a cysteine protease. Endogenous proteases may contribute to clinical pruritus and pain. Using, among other stimuli, a new method of punctate application of a chemical that has been loaded into a heat-inactivated spicule of cowhage, we will psychophysically measure itch, pain and itchy skin (enhanced itch or pain) in human volunteers.
Our aims are the following: (1) We will determine whether itch, pain, and cutaneous dysesthesias (enhanced itch or pain) from punctate application of mechanical or chemical pruritic stimuli such as an endogenous cysteine protease, are mediated by capsaicin sensitive primary afferent neurons;(2) We will test whether co-activation of the histaminergic and non-histaminergic pathways leads to the prolongation or enhancement of pruritic and nociceptive sensations and dysesthesias;(3) We will study the inhibitory effects of scratching, heating and algogenic chemicals on itch, pain and itchy skin while teasing apart the separate roles of stimulus modality (type of neuron activated), locus and intensity. (4) We will us a pressure block of conduction in myelinated nerve fibers to exam the separate roles of nociceptors with myelinated vs. non? myelinated axons in chemically and mechanically evoked itch, nociceptive sensations and dysesthesias. The outcomes of these studies will increase understanding of how itch and pain and dysesthetic states can co? exist as in certain clinical disorders;and how one or another sensory quality or dysesthetic state can be enhanced or inhibited. These psychophysical studies in human will provide a set of sensory conditions that must be accounted for by the responses of candidate pruriceptive and nociceptive-specific sensory neurons in the peripheral and central nervous system.

Public Health Relevance

Psychophysical measurements of experimentally produced itch, pain and itchy skin in humans will further our understanding of the sensory conditions contributing to clinical pruritus and point to their underlying neural mechanisms. These mechanisms provide targets for future pharmacological therapies designed to relieve 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 #
8375827
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$275,640
Indirect Cost
$64,350
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Yu, Chang; Zelterman, Daniel (2017) A parametric model to estimate the proportion from true null using a distribution for p-values. Comput Stat Data Anal 114:105-118
LaMotte, Robert H (2016) Allergic Contact Dermatitis: A Model of Inflammatory Itch and Pain in Human and Mouse. Adv Exp Med Biol 904:23-32
Lipshetz, Brett; Giesler Jr, Glenn J (2016) Effects of scratching and other counterstimuli on responses of trigeminothalamic tract neurons to itch-inducing stimuli in rats. J Neurophysiol 115:520-9
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
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
Crawford, Forrest W; Zelterman, Daniel (2015) Markov counting models for correlated binary responses. Biostatistics 16:427-40
Pall, Parul S; Hurwitz, Olivia E; King, Brett A et al. (2015) Psychophysical measurements of itch and nociceptive sensations in an experimental model of allergic contact dermatitis. J Pain 16:741-9
Moser, Hannah R; Giesler Jr, Glenn J (2014) Characterization of pruriceptive trigeminothalamic tract neurons in rats. J Neurophysiol 111:1574-89
Ringkamp, Matthias; Raja, Srinivasa N (2014) A sore spot: central or peripheral generation of chronic neuropathic spontaneous pain? Pain 155:1189-91

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