Our recent studies of modulation of purinergic receptors (P2XR) in dorsal root ganglion (DRG) neurons show that, after inflammation or nerve injury, the activity of P2X3Rs becomes greatly enhanced The increase derives either from an upregulation of P2X3R expression or an increase in the trafficking of P2X3Rs to the cell membrane. This receptor sensitization contributes to abnormal pain responses in rat pain models. We further show that inflammation changes the modulatory signaling of P2X3Rs. Prostaglandin E2 (PGE2) modulation of P2X3Rs switches from a solely PKA-dependent to both PKA and PKC-dependent signaling as a result of the activation of cAMP-regulated guanine nucleotide exchange protein (Epac). Our focus here is to understand the role that Epac may have in changing P2X3R expression and trafficking. We hypothesize that injury facilitates Epac activation. Interactions among Epac, cytoskeletal proteins and scaffold anchoring protein complexes play critical roles in the modulation of P2X3R activity. In vitro and in vivo approaches will be used to test this hypothesis. We will determine if Epac interacts with P2X3Rs, actin and AKAP in DRGs and if injury changes the interactions. We will further determine if these proteins participate in the modulation of P2X3R-mediated current responses. In addition, we will determine if blocking Epac activity can reduce abnormal pain behaviors in rats. These studies should provide a better understanding of the mechanisms underlying injury-induced P2XR sensitization.

Public Health Relevance

This project is designed to understand how neurons become excessively sensitive to stimuli after injury, a phenomenon contributing to chronic pain conditions. The study will identify proteins that control the sensitization and suggest more effective treatments for severe and chronic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030045-16
Application #
8314107
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
1993-01-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
16
Fiscal Year
2012
Total Cost
$327,994
Indirect Cost
$113,619
Name
University of Texas Medical Br Galveston
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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Gu, Yanping; Xu, Ya; Li, Guang-Wen et al. (2005) Remote nerve injection of mu opioid receptor adeno-associated viral vector increases antinociception of intrathecal morphine. J Pain 6:447-54

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