Touch sensation is essential to daily life. Further, hypersensitivity to touch is a frequent problem associated with chronic neuropathic pain and persistent inflammatory pain. Despite its importance, amazingly little is known about the molecular and cellular mechanisms underlying touch sensation and whether different transduction mechanisms mediate innocuous versus painful mechanical stimuli. A promising mechanotransduction candidate is the Transient Receptor Potential Ankyrin 1 (TRPA1). Significant evidence suggests that TRPA1 contributes to mechanotransduction in somatosensory neurons and their sensitization to mechanical stimuli after tissue inflammation or nerve injury. Further, controversial evidence suggests that TRPA1 is involved in cold transduction and cold sensitization after nerve injury and inflammation. A number of important questions remain, however, about the specific functional roles of TRPA1 in mechanotransduction and cold transduction. 1) Evidence from our laboratory and others indicates that TRPA1 is expressed by non- neuronal keratinocytes, as well as sensory nerve terminals, yet the contribution of TRPA1 in either cell type to the net responses of cutaneous primary afferent neurons to mechanical force or cold temperatures is unknown. Experiments in this proposal will use two new lines of transgenic mice where TRPA1 is selectively deleted from either keratinocytes or sensory neurons to determine the contribution of TRPA1 in either cell type to behavioral and primary afferent fiber responses to mechanical and cold stimuli. 2) Whether TRPA1 in sensory neurons or keratinocytes mediates the plasma membrane response to mechanical force or cold is not clear. Experiments in this application will use an innovative, quantitative focal mechanical stimulator during whole cell patch clamp recordings to identify the contribution of TRPA1 to mechanical currents in the membrane of sensory neurons and keratinocytes. 3) Mechanical hypersensitivity is one of the most frequent, devastating symptoms associated with neuropathic and inflammatory pain. The contribution of TRPA1 to sensitization of primary afferent fibers to mechanical and cold stimuli after nerve injury or inflammation is unknown. Experiments in this proposal will determine whether TRPA1 in either sensory neurons or keratinocytes mediates the mechanical or cold sensitization that occurs in a model of neuropathic pain, and a model of persistent peripheral inflammation. In this proposal, complimentary Specific Aims using cellular, teased fiber and behavioral assays will provide a multifaceted approach to identify functional roles of TRPA1 in sensory transduction in normal tissue, and during neuropathic and inflammatory pain.

Public Health Relevance

Touch sensation is essential to daily life. Abnormal hypersensitivity to touch and to cold temperature occurs in patients with chronic neuropathic pain and persistent inflammatory pain syndromes. Our goals are to determine the roles of the ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) in touch and cold transduction in normal skin, and to identify its roles in neuropathic and inflammatory pain models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040538-13
Application #
8600731
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Chen, Daofen
Project Start
2000-07-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
13
Fiscal Year
2014
Total Cost
$301,219
Indirect Cost
$104,344
Name
Medical College of Wisconsin
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
Sadler, Katelyn E; Zappia, Katherine J; O?Hara, Crystal L et al. (2018) Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice. Pain 159:1652-1663
Moehring, Francie; Cowie, Ashley M; Menzel, Anthony D et al. (2018) Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. Elife 7:
Sadler, Katelyn E; Stucky, Cheryl L (2018) Neuronal transient receptor potential (TRP) channels and noxious sensory detection in sickle cell disease. Neurosci Lett 694:184-191
Moehring, Francie; Waas, Matthew; Keppel, Theodore R et al. (2018) Quantitative Top-Down Mass Spectrometry Identifies Proteoforms Differentially Released during Mechanical Stimulation of Mouse Skin. J Proteome Res 17:2635-2648
Miller, James J; Aoki, Kazuhiro; Moehring, Francie et al. (2018) Neuropathic pain in a Fabry disease rat model. JCI Insight 3:
Brandow, Amanda M; Hansen, Karla; Nugent, Melodee et al. (2018) Children and adolescents with sickle cell disease have worse cold and mechanical hypersensitivity during acute painful events. Pain :
Moehring, Francie; Halder, Priyabrata; Seal, Rebecca P et al. (2018) Uncovering the Cells and Circuits of Touch in Normal and Pathological Settings. Neuron 100:349-360
Cowie, Ashley M; Moehring, Francie; O'Hara, Crystal et al. (2018) Optogenetic Inhibition of CGRP? Sensory Neurons Reveals Their Distinct Roles in Neuropathic and Incisional Pain. J Neurosci 38:5807-5825
Zappia, Katherine J; O'Hara, Crystal L; Moehring, Francie et al. (2017) Sensory Neuron-Specific Deletion of TRPA1 Results in Mechanical Cutaneous Sensory Deficits. eNeuro 4:
Xiang, Hongfei; Liu, Zhen; Wang, Fei et al. (2017) Primary sensory neuron-specific interference of TRPV1 signaling by AAV-encoded TRPV1 peptide aptamer attenuates neuropathic pain. Mol Pain 13:1744806917717040

Showing the most recent 10 out of 66 publications