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
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:
Brandow, Amanda M; Zappia, Katherine J; Stucky, Cheryl L (2017) Sickle cell disease: a natural model of acute and chronic pain. Pain 158 Suppl 1:S79-S84
Zappia, Katherine J; Guo, Yihe; Retherford, Dawn et al. (2017) Characterization of a mouse model of sickle cell trait: parallels to human trait and a novel finding of cutaneous sensitization. Br J Haematol 179:657-666
Zappia, Katherine J; Garrison, Sheldon R; Palygin, Oleg et al. (2016) Mechanosensory and ATP Release Deficits following Keratin14-Cre-Mediated TRPA1 Deletion Despite Absence of TRPA1 in Murine Keratinocytes. PLoS One 11:e0151602
Moehring, Francie; O'Hara, Crystal L; Stucky, Cheryl L (2016) Bedding Material Affects Mechanical Thresholds, Heat Thresholds, and Texture Preference. J Pain 17:50-64
Weyer, Andy D; Zappia, Katherine J; Garrison, Sheldon R et al. (2016) Nociceptor Sensitization Depends on Age and Pain Chronicity(1,2,3). eNeuro 3:
Osteen, Jeremiah D; Herzig, Volker; Gilchrist, John et al. (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534:494-9
Weyer, Andy D; O'Hara, Crystal L; Stucky, Cheryl L (2015) Amplified Mechanically Gated Currents in Distinct Subsets of Myelinated Sensory Neurons following In Vivo Inflammation of Skin and Muscle. J Neurosci 35:9456-62
Morita, Takeshi; McClain, Shannan P; Batia, Lyn M et al. (2015) HTR7 Mediates Serotonergic Acute and Chronic Itch. Neuron 87:124-38
Aboualizadeh, Ebrahim; Mattson, Eric C; O'Hara, Crystal L et al. (2015) Cold shock induces apoptosis of dorsal root ganglion neurons plated on infrared windows. Analyst 140:4046-56

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