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 #
5R01NS040538-12
Application #
8410091
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
2013-01-01
Budget End
2013-12-31
Support Year
12
Fiscal Year
2013
Total Cost
$322,974
Indirect Cost
$111,880
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
Garrison, Sheldon R; Stucky, Cheryl L (2014) Contribution of transient receptor potential ankyrin 1 to chronic pain in aged mice with complete Freund's adjuvant-induced arthritis. Arthritis Rheumatol 66:2380-90
Woo, Seung-Hyun; Ranade, Sanjeev; Weyer, Andy D et al. (2014) Piezo2 is required for Merkel-cell mechanotransduction. Nature 509:622-6
Barabas, Marie E; Mattson, Eric C; Aboualizadeh, Ebrahim et al. (2014) Chemical structure and morphology of dorsal root ganglion neurons from naive and inflamed mice. J Biol Chem 289:34241-9
Garrison, Sheldon R; Weyer, Andy D; Barabas, Marie E et al. (2014) A gain-of-function voltage-gated sodium channel 1.8 mutation drives intense hyperexcitability of A- and C-fiber neurons. Pain 155:896-905
Dranka, Brian P; Gifford, Alison; McAllister, Donna et al. (2014) A novel mitochondrially-targeted apocynin derivative prevents hyposmia and loss of motor function in the leucine-rich repeat kinase 2 (LRRK2(R1441G)) transgenic mouse model of Parkinson's disease. Neurosci Lett 583:159-64
Zappia, Katherine J; Garrison, Sheldon R; Hillery, Cheryl A et al. (2014) Cold hypersensitivity increases with age in mice with sickle cell disease. Pain 155:2476-85
McGivern, Jered V; Patitucci, Teresa N; Nord, Joshua A et al. (2013) Spinal muscular atrophy astrocytes exhibit abnormal calcium regulation and reduced growth factor production. Glia 61:1418-28
Tsunozaki, Makoto; Lennertz, Richard C; Vilceanu, Daniel et al. (2013) A 'toothache tree' alkylamide inhibits Aýý mechanonociceptors to alleviate mechanical pain. J Physiol 591:3325-40
Barabas, Marie E; Stucky, Cheryl L (2013) TRPV1, but not TRPA1, in primary sensory neurons contributes to cutaneous incision-mediated hypersensitivity. Mol Pain 9:9
Gemes, Geza; Koopmeiners, Andrew; Rigaud, Marcel et al. (2013) Failure of action potential propagation in sensory neurons: mechanisms and loss of afferent filtering in C-type units after painful nerve injury. J Physiol 591:1111-31

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