Peripheral neuropathic pain affects over 3.8 million in the US and is one of the most challenging forms of chronic pain to manage, primarily because the underlying physiological and molecular mechanisms are poorly understood. A better understanding of basic mechanisms underlying pain will lead to the development of novel pain therapies. Stimulus-evoked pain is initiated in primary afferent fibers that remain intact after nerve injury, but little is known about functional changes that occur in intact, adjacent neurons to natural heat or mechanical stimuli after injury. Therefore, an overall goal of this proposal is to define functional changes in intact cutaneous primary afferent neurons that contribute to peripheral neuropathic pain. The Transient Receptor Potential Vanilloid 1 (TRPV1) receptor is a fundamental molecular integrator of physical and chemical, external and endogenous stimuli for cutaneous afferent neurons. TRPV1 unequivocally contributes to inflammatory heat hyperalgesia, but far less is known about the role(s) of TRPV1 in nerve injury pain. Several lines of preliminary data from my laboratory and others strongly suggest that TRPV1 contributes to both the heat hyperalgesia and mechanical allodynia that accompanies nerve injury. Therefore, this proposal will test the overall hypothesis that TRPV1 plays a role in nerve injury- induced pain behavior by contributing to the sensitization of adjacent intact primary afferent neurons to heat and mechanical stimuli and the expression of spontaneous activity following nerve injury. By using behavioral assays and electrophysiological recording techniques at the soma and terminal of the cutaneous sensory neuron, and by conducting parallel experiments in wild type mice treated with a novel, highly selective TRPV1 antagonist and in TRPV1 null mice, we will test the following three specific hypotheses: 1) TRPV1 contributes to nerve injury-induced heat and mechanical behavioral hypersensitivity;2) TRPV1 contributes to nerve injury-induced heat sensitization of intact cutaneous primary afferent neurons at the level of the nerve terminal and the soma;3) TRPV1 contributes to nerve injury-induced spontaneous activity and mechanical sensitization of intact cutaneous afferent neurons. Understanding the role of TRPV1 in nerve injury-induced pain behavior sensitization of primary sensory neurons will contribute to the development and use of novel TRPV1 antagonists in patients with neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040538-09
Application #
7753619
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2000-07-01
Project End
2011-01-14
Budget Start
2010-01-01
Budget End
2011-01-14
Support Year
9
Fiscal Year
2010
Total Cost
$294,913
Indirect Cost
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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