Our recent studies of the communication between neuronal soma and satellite glial cells (SGCs) in dorsal root ganglia (DRGs) suggest that somatic release of ATP in response to afferent nerve stimulation activates purinergic P2X7 receptors (P2X7Rs) in SGCs. Under normal conditions, tonic activation of P2X7Rs in SGCs reduces P2X3R expression in neuronal somata, thus exerting inhibitory control of neuronal activity. Following high frequency nerve stimulation, activation of P2X7Rs evokes cytokine release causing an enhancement of P2X3R activity in somata and an increase in the excitability of neurons. The P2X7R-mediated SGC-neuronal soma feedback controls under inflammation and nerve injury conditions have not been well established. This knowledge is essential for understanding the generation and maintenance of abnormal chronic pain. The goal of this application is to understand changes in neuronal soma-SGC communication during different phases of chronic pain development. We hypothesize that following injury, an increase in cytokine release switches P2Rmediated SGC-soma communication from inhibitory to excitatory feedback control, thus initiating the development of abnormal pain states. A subsequent large increase in ATP release, which activates P2X7Rs and pannexin-1, produces a large enhancement of SGC-soma communication and thus leads to the transition from the development to the maintenance phase of chronic pain. We will (1) determine if P2R-mediated SGC-soma communication changes during the development and maintenance phase of chronic pain, (2) determine the mechanisms underlying the change in SGC-soma communication and (3) determine if modulation of SGC-soma communication is a valid strategy for the management of chronic pain.

Public Health Relevance

This project is designed to understand the mechanism underlying the over-excitation of sensory neurons after injury, a phenomenon contributing to chronic pain conditions. The study will determine injury-induced changes in neuron-glial cell communication and suggest better therapeutic targets for chronic pain control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
2R01DE017813-07A1
Application #
8506629
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Kusiak, John W
Project Start
2006-07-15
Project End
2018-03-31
Budget Start
2013-05-15
Budget End
2014-03-31
Support Year
7
Fiscal Year
2013
Total Cost
$386,250
Indirect Cost
$136,250
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
Gu, Yanping; Wang, Congying; Li, Guangwen et al. (2016) EXPRESS: F-actin links Epac-PKC signaling to purinergic P2X3 receptors sensitization in dorsal root ganglia following inflammation. Mol Pain 12:
Gu, Yanping; Li, Guangwen; Chen, Yong et al. (2016) Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation. Pain 157:1541-50
Chen, Yong; Li, Guangwen; Huang, Li-Yen Mae (2015) p38 MAPK mediates glial P2X7R-neuronal P2Y1R inhibitory control of P2X3R expression in dorsal root ganglion neurons. Mol Pain 11:68
Huang, Li-Yen M; Gu, Yanping; Chen, Yong (2013) Communication between neuronal somata and satellite glial cells in sensory ganglia. Glia 61:1571-81
Li, Guangwen; Ma, Fei; Gu, Yanping et al. (2013) Analgesic tolerance of opioid agonists in mutant mu-opioid receptors expressed in sensory neurons following intrathecal plasmid gene delivery. Mol Pain 9:63
Chen, Yong; Li, Guangwen; Huang, Li-Yen Mae (2012) P2X7 receptors in satellite glial cells mediate high functional expression of P2X3 receptors in immature dorsal root ganglion neurons. Mol Pain 8:9
Wilkes, Denise; Li, Guangwen; Angeles, Carmina F et al. (2012) A large animal neuropathic pain model in sheep: a strategy for improving the predictability of preclinical models for therapeutic development. J Pain Res 5:415-24
Gu, Yanping; Chen, Yong; Zhang, Xiaofei et al. (2010) Neuronal soma-satellite glial cell interactions in sensory ganglia and the participation of purinergic receptors. Neuron Glia Biol 6:53-62
Wang, Congying; Li, Guang-Wen; Huang, Li-Yen Mae (2007) Prostaglandin E2 potentiation of P2X3 receptor mediated currents in dorsal root ganglion neurons. Mol Pain 3:22
Zhang, X; Chen, Y; Wang, C et al. (2007) Neuronal somatic ATP release triggers neuron-satellite glial cell communication in dorsal root ganglia. Proc Natl Acad Sci U S A 104:9864-9

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