Neuropathic pain caused by trauma and surgery is a major clinical problem and remains difficult to treat. Neuronal plasticity at the spinal cord level is fundamentally important to the development of neuropathic pain caused by nerve injury. N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels critically involved in central sensitization and maintenance of neuropathic pain. However, the molecular mechanisms underlying potentiated NMDAR activity in the spinal dorsal horn after nerve injury remain poorly understood. ?2?-1, commonly known as a subunit of voltage-activated calcium channels, is upregulated in the dorsal root ganglion and spinal dorsal horn after nerve injury. Although ?2?-1 upregulation contributes to neuropathic pain, little is known about the mechanisms through which ?2?-1 is involved in neuropathic pain development. In our preliminary studies, we found that ?2?-1 physically interacted with NMDAR subunits and that siRNA knockdown of ?2?-1 profoundly attenuated spinal cord NMDAR activity increased by nerve injury. Furthermore, gabapentin treatment interrupted the ?2?-1 and NMDAR association and normalized nerve injury?induced potentiation of spinal NMDAR activity. In this proposal, we will use a multidisciplinary approach to test our central hypothesis that nerve injury?induced ?2?-1 upregulation critically contributes to potentiation of spinal NMDAR activity and development of neuropathic pain by physically interacting with NMDARs and that gabapentinoids attenuate nerve injury?induced pain hypersensitivity and NMDAR activity at the spinal cord level by disrupting the ?2?-1?NMDAR physical association. Our project is expected to generate substantial new information to unravel a novel function of ?2?-1 as a potent regulatory protein of NMDARs and to identify the important role of ?2?-1?NMDAR complexes in the development of neuropathic pain. Because our studies will provide new molecular insight into mechanisms of neuropathic pain and gabapentinoid actions, our project is highly innovative and underscores a major conceptual advance in understanding the molecular composition, heterogeneity, and function of native NMDARs and synaptic plasticity. We expect that these new findings will significantly advance our understanding of the molecular mechanisms of neuropathic pain and lead to the development of new strategies to treat chronic neuropathic pain.

Public Health Relevance

Chronic neuropathic pain remains a major clinical problem, and available pain medications have limited effects. This application seeks to define the role of a key protein-protein interaction involved in regulating glutamate receptor activity associated with neuropathic pain development and in the effects of gabapentin-like drugs. Findings from this proposal not only can improve our understanding of the cellular and molecular mechanisms of neuropathic pain but also can help the development of improved therapies for treating neuropathic pain.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM120844-04
Application #
9743851
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Justinova, Zuzana
Project Start
2016-08-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Anesthesiology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Chen, Youfang; Chen, Shao-Rui; Chen, Hong et al. (2018) Increased ?2?-1-NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy-induced neuropathic pain. J Neurochem :
Wang, Li; Chen, Shao-Rui; Ma, Huijie et al. (2018) Regulating nociceptive transmission by VGluT2-expressing spinal dorsal horn neurons. J Neurochem 147:526-540
Chen, Jinjun; Li, Lingyong; Chen, Shao-Rui et al. (2018) The ?2?-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions. Cell Rep 22:2307-2321
Xie, Jing-Dun; Chen, Shao-Rui; Chen, Hong et al. (2017) Bortezomib induces neuropathic pain through protein kinase C-mediated activation of presynaptic NMDA receptors in the spinal cord. Neuropharmacology 123:477-487
Chen, Jinjun; Pan, Hui-Lin (2017) Dissecting molecular architecture of post-synaptic density at excitatory synapses: An Editorial Highlight for 'Hierarchical organization and genetically separable subfamilies of PSD95 postsynaptic supercomplexes' on page 504. J Neurochem 142:500-503
Xie, Jing-Dun; Chen, Shao-Rui; Pan, Hui-Lin (2017) Presynaptic mGluR5 receptor controls glutamatergic input through protein kinase C-NMDA receptors in paclitaxel-induced neuropathic pain. J Biol Chem 292:20644-20654
Chen, Shao-Rui; Jin, Xiao-Gao; Pan, Hui-Lin (2017) Endogenous nitric oxide inhibits spinal NMDA receptor activity and pain hypersensitivity induced by nerve injury. Neuropharmacology 125:156-165