How dysfunctional glial cells lead to abnormal pain signaling in the spinal dorsal horn in neuropathic pain remains a mystery. Activation of glutamate receptors by glutamate is a key step for acute pain transmission and activation of signal transduction pathways leading to initiation and maintenance of pathological pain. Activation of glutamate receptors is governed by three essential factors: the amount of synaptically released glutamate, the rate at which glutamate is removed by glutamate transporters (GTs) and the properties of postsynaptic glutamate receptors. Modern pain treatments directed at the transmission of pain singals have mainly focused either on the presynaptic levels to block glutamate release from presynaptic terminals or on the postsynaptic levels to block glutamate receptors and glutamate activated signal transduction pathways in postsynaptic neurons. Targeting at GTs to correct abnormal activation of glutamate receptors has been much less investigated. One key role for glial cells in regulating signal transmission at the glutamatergic synapse is the removal of synaptic glutamate by glial GTs. Studies on the forebrain have demonstrated that glial GT accounts for more than 94% of all CNS synaptic glutamate uptake and is a key machinery regulating synaptic signal transmission and plasticity. However, the role of glial GTs in regulating synaptic transmission in the spinal dorsal horn and their contribution to abnormal pain signaling have not been established. Based on our preliminary findings, we hypothesize that activation of glial cells induced by nerve injury results in dysfunction of glial GTs, which leads to abnormal activation of ionotropic glutamate receptors in the spinal dorsal horn and behavioral hypersensitivity. This hypothesis will be tested with three specific aims.
Specific Aim 1 will determine the relationships between glial GT expression and development of behavioral hypersensitivity, glial activation and release of pro-inflammatory cytokines induced by nerve injury.
Specific Aim 2 will determine the contribution of deficient glutamate uptake by glial GTs to abnormal activation of AMPA and NMDA receptors in the spinal dorsal horn and behavioral hypersensitivity in neuropathic rats.
Specific Aim 3 will determine the contribution of recovered glutamate uptake by glial GTs to the """"""""normalized"""""""" activation of ionotropic glutamate receptors in the spinal dorsal horn and to the """"""""normalized"""""""" nociceptive behaviors in neuropathic rats after treatments of glial inhibitors or antagonists for pro-inflammatory cytokines. Experiments will be conducted in control (normal naove and sham operated) rats and neuropathic rats induced by partial sciatic nerve ligation, which is known to mimic neuropathic pain induced by partial nerve injury in patients. Multi-disciplinary- techniques, including visualized whole cell voltage clamp recordings from spinal slices, pharmacology, immunohistochemistry and behavioral tests will be applied to test our hypothesis. The proposed study will provide new insights into the synaptic and molecular mechanisms underlying glial-cytokine-neuronal interactions in neuropathic pain and may potentially lead to the use of GTs as a new target for reducing persistent and abnormal activation of glutamate receptors in the management of chronic pain.

Public Health Relevance

How dysfunctional glial cells lead to abnormal pain signaling in the spinal dorsal horn in neuropathic pain remains a mystery. Activation of glutamate receptors by glutamate is a key step for acute pain transmission and activation of signal transduction pathways leading to initiation and maintenance of pathological pain. We hypothesize that activation of glial cells induced by nerve injury results in dysfunction of glial GTs, which leads to abnormal activation of ionotropic glutamate receptors in the spinal dorsal horn and behavioral hypersensitivity. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS064289-02
Application #
7894530
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Porter, Linda L
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$300,155
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Stockstill, Katherine; Doyle, Timothy M; Yan, Xisheng et al. (2018) Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med 215:1301-1313
Yadav, Ruchi; Weng, Han-Rong (2017) EZH2 regulates spinal neuroinflammation in rats with neuropathic pain. Neuroscience 349:106-117
Alqinyah, Mohammed; Maganti, Nagini; Ali, Mourad W et al. (2017) Regulator of G Protein Signaling 10 (Rgs10) Expression Is Transcriptionally Silenced in Activated Microglia by Histone Deacetylase Activity. Mol Pharmacol 91:197-207
Yan, Xisheng; Maixner, Dylan W; Li, Fen et al. (2017) Chronic pain and impaired glial glutamate transporter function in lupus-prone mice are ameliorated by blocking macrophage colony-stimulating factor-1 receptors. J Neurochem 140:963-976
Maixner, Dylan W; Yan, Xisheng; Hooks, Shelley B et al. (2016) AMPK?1 knockout enhances nociceptive behaviors and spinal glutamatergic synaptic activities via production of reactive oxygen species in the spinal dorsal horn. Neuroscience 326:158-169
Maixner, Dylan W; Yan, Xisheng; Gao, Mei et al. (2015) Adenosine Monophosphate-activated Protein Kinase Regulates Interleukin-1? Expression and Glial Glutamate Transporter Function in Rodents with Neuropathic Pain. Anesthesiology 122:1401-13
Yan, Xisheng; Maixner, Dylan W; Yadav, Ruchi et al. (2015) Paclitaxel induces acute pain via directly activating toll like receptor 4. Mol Pain 11:10
Yadav, Ruchi; Yan, Xisheng; Maixner, Dylan W et al. (2015) Blocking the GABA transporter GAT-1 ameliorates spinal GABAergic disinhibition and neuropathic pain induced by paclitaxel. J Neurochem 133:857-69
Yan, Xisheng; Jiang, Enshe; Weng, Han-Rong (2015) Activation of toll like receptor 4 attenuates GABA synthesis and postsynaptic GABA receptor activities in the spinal dorsal horn via releasing interleukin-1 beta. J Neuroinflammation 12:222
Weng, Han-Rong; Gao, Mei; Maixner, Dylan W (2014) Glycogen synthase kinase 3 beta regulates glial glutamate transporter protein expression in the spinal dorsal horn in rats with neuropathic pain. Exp Neurol 252:18-27

Showing the most recent 10 out of 20 publications