The peripheral mechanisms of inflammatory itch and pain will be studied in a mouse model of allergic contact dermatitis (ACD) in humans. ACD is a Type IV delayed hypersensitivity reaction initiated by T lymphocytes specific for an allergen. ACD is a significant clinical problem and a major occupational disease affecting millions of people worldwide each year and seriously impacting their quality of life. Despite extensive biological studies of the inflammatory mechanisms causing ACD, there have been few if any studies of the peripheral sensory neurons and their abnormal hyperexcitability and ongoing activity that contribute to the itch and pain of ACD. Preliminary electrophsiological recordings from candidate pruriceptive mechanosensitive neurons in the mouse reveal membrane hyperexcitability (dissociated neurons in vitro) and spontaneous activity (in vivo) after experimentally produced ACD. We will test the hypothesis that this hyperexcitability renders neurons more responsive to endogenous chemicals such as the chemokines that orchestrate the elicitation of ACD. We will use transgenic fluorescent markers combined with recordings of electrophysiological or activated calcium responses, to identify and characterize, both in vivo and in vitro, specific subtypes of pruriceptive/nociceptive cutaneous peripheral sensory neurons. We will determine the ionic mechanisms contributing to the hyperexcitability and test the increased efficacy of certain chemokines to directly excite neurons after ACD. We will also test the efficacy of chemokine receptor antagonists in reducing both the in-vivo neuronal hyperexcitability and the spontaneous itch and nociceptive behavior that accompany ACD. The outcomes will generate new peripheral neuronal targets, and new ion channels and receptors to target for the treatment of inflammatory itch and pain.

Public Health Relevance

Although allergic contact dermatitis (ACD) is a significant clinical problem affecting millions of people worldwide, there are few if any studies of the neuronal basis for the pain and itch associated with the disease. Using a translational mouse model of ACD in humans, we will identify and characterize itch- and pain mediating peripheral sensory neurons that become hyperexcitable after ACD. We will determine the ionic mechanisms of this hyperexcitability, test for the capacity of certain chemotactic chemokines, known to orchestrate the inflammation of ACD, to also directly excite sensory neurons. We will also test the efficacy of chemokine receptor antagonists in reducing the neuronal hyperexcitability and the spontaneous itch and nociceptive behavior that accompany ACD. The outcomes will generate new peripheral neuronal targets, and new ion channels and receptors to target, for the treatment of inflammatory itch and pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS014624-35
Application #
8535828
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Daofen
Project Start
1978-07-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
35
Fiscal Year
2013
Total Cost
$413,484
Indirect Cost
$165,145
Name
Yale University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Fu, Kai; Qu, Lintao; Shimada, Steven G et al. (2014) Enhanced scratching elicited by a pruritogen and an algogen in a mouse model of contact hypersensitivity. Neurosci Lett 579:190-4
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
Han, Liang; Ma, Chao; Liu, Qin et al. (2013) A subpopulation of nociceptors specifically linked to itch. Nat Neurosci 16:174-82
Pan, Xinghua; Durrett, Russell E; Zhu, Haiying et al. (2013) Two methods for full-length RNA sequencing for low quantities of cells and single cells. Proc Natl Acad Sci U S A 110:594-9
Ma, C; Nie, H; Gu, Q et al. (2012) In vivo responses of cutaneous C-mechanosensitive neurons in mouse to punctate chemical stimuli that elicit itch and nociceptive sensations in humans. J Neurophysiol 107:357-63
Fan, Ni; Donnelly, David F; LaMotte, Robert H (2011) Chronic compression of mouse dorsal root ganglion alters voltage-gated sodium and potassium currents in medium-sized dorsal root ganglion neurons. J Neurophysiol 106:3067-72
LaMotte, Robert H; Shimada, Steven G; Sikand, Parul (2011) Mouse models of acute, chemical itch and pain in humans. Exp Dermatol 20:778-82
Qu, Lintao; Zhang, Pu; LaMotte, Robert H et al. (2011) Neuronal Fc-gamma receptor I mediated excitatory effects of IgG immune complex on rat dorsal root ganglion neurons. Brain Behav Immun 25:1399-407
Ma, Chao; Donnelly, David F; LaMotte, Robert H (2010) In vivo visualization and functional characterization of primary somatic neurons. J Neurosci Methods 191:60-5

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