Abstract

Neuropathic pain is a chronic and debilitating disease that is difficult to treat with existing analgesics. Recent studies reveal a critical role for lysophosphatidic acid (LPA) receptor activation in causing neuropathic pain. We found that many small diameter, presumably nociceptive, dorsal root ganglia (DRG) and trigeminal neurons express a transmembrane-localized phosphatase that dephosphorylates LPA. Based on these observations, our long term research objectives are to demonstrate that this phosphatase modulates LPA receptor signaling in vitro, using cultured sensory neurons, and in vivo, using mouse neuropathic pain models. To accomplish this, we will first use immunohistochemistry to characterize the sensory neurons that express this phosphatase and identify the peripheral tissues that are innervated by phosphatase-containing afferents. Next, we will test the hypothesis that this phosphatase modulates LPA receptor signaling in cell lines and in dissociated mouse DRG neurons using calcium imaging and luciferase reporter gene assays. We will use genetically modified mice expressing Green Fluorescent Protein to identify the DRG neurons that express this phosphatase. Finally, we will test the hypothesis that this phosphatase modulates neuropathic pain behaviors in wild-type and phosphatase knockout mice. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS060725-02
Application #
7501935
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2007-09-30
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2009-08-31
Support Year
2
Fiscal Year
2008
Total Cost
$317,091
Indirect Cost

  Institution

Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599

  Publications

McCoy, Eric S; Taylor-Blake, Bonnie; Street, Sarah E et al. (2013) Peptidergic CGRP? primary sensory neurons encode heat and itch and tonically suppress sensitivity to cold. Neuron 78:138-51
Kokel, David; Cheung, Chung Yan J; Mills, Robert et al. (2013) Photochemical activation of TRPA1 channels in neurons and animals. Nat Chem Biol 9:257-63
Hurt, Julie K; Zylka, Mark J (2012) PAPupuncture has localized and long-lasting antinociceptive effects in mouse models of acute and chronic pain. Mol Pain 8:28
Rittiner, Joseph E; Korboukh, Ilia; Hull-Ryde, Emily A et al. (2012) AMP is an adenosine A1 receptor agonist. J Biol Chem 287:5301-9
Hurt, Julie K; Fitzpatrick, Brendan J; Norris-Drouin, Jacqueline et al. (2012) Secretion and N-linked glycosylation are required for prostatic acid phosphatase catalytic and antinociceptive activity. PLoS One 7:e32741
McCoy, Eric S; Taylor-Blake, Bonnie; Zylka, Mark J (2012) CGRP?-expressing sensory neurons respond to stimuli that evoke sensations of pain and itch. PLoS One 7:e36355
Street, Sarah E; Walsh, Paul L; Sowa, Nathaniel A et al. (2011) PAP and NT5E inhibit nociceptive neurotransmission by rapidly hydrolyzing nucleotides to adenosine. Mol Pain 7:80
Mabb, Angela M; Judson, Matthew C; Zylka, Mark J et al. (2011) Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes. Trends Neurosci 34:293-303
Huang, Hsien-Sung; Allen, John A; Mabb, Angela M et al. (2011) Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481:185-9
Zylka, Mark J (2011) Pain-relieving prospects for adenosine receptors and ectonucleotidases. Trends Mol Med 17:188-96

Showing the most recent 10 out of 22 publications