Neuropathic pain caused by trauma and surgery is a significant health problem. Since chronic neuropathic pain often is inadequately relieved by conventional analgesics, its treatment represents an important unmet clinical need. The major objective of this grant renewal is to determine the role of groups II and III metabotropic glutamate receptor (mGluR) subtypes in the regulation of spinal synaptic transmission and nociception in neuropathic pain. Increased glutamatergic input to spinal dorsal horn neurons is critically involved in development of neuropathic pain. However, little is known about the contribution of groups II and mGluR subtypes in the spinal cord to central sensitization and neuropathic pain.
The specific aims of this project are to: (1) determine the mGluR subtypes that mediate the therapeutic effect of spinally administered group II and III mGluR agonists on allodynia and hyperalgesia and hyperactivity of dorsal horn neurons in neuropathic pain; (2) examine the temporal changes in groups II and III mGluR subtypes in the spinal dorsal horn after nerve injury and define the contribution of individual groups II and III mGluR subtypes in the spinal cord to neuropathic pain symptoms; (3) determine the role of groups II and III mGluR subtypes in the spinal cord in the regulation of glutamatergic and GABAergic transmission in neuropathic pain; and (4) identify the distinct signaling mechanisms of the presynaptic actions of groups II and III mGluRs in the feedback control of synaptic glutamate release to spinal dorsal horn neurons. Our overall hypothesis is that nerve injury decreases presynaptic groups II and III mGluRs in the spinal dorsal horn and that downregulation of these mGluRs contributes to increased glutamatergic input and hypersensitivity of spinal dorsal horn neurons in neuropathic pain. To test this hypothesis, we will use many state-of-the-art approaches, including electrophysiological recording of dorsal horn neurons in vivo, whole-cell patch-clamp recordings in spinal cord slices, measurements of mGluR expression, spinal mGluR gene silencing with siRNAs, and behavioral assessment of nociception. The proposed studies are important for a better understanding of the cellular and molecular mechanisms of spinal synaptic plasticity in neuropathic pain. The novel information gained also will provide a rationale for development of new subtype-specific groups II and III mGluR agonists to treat patients with intractable neuropathic pain. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM064830-06
Application #
7489487
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2001-05-01
Project End
2011-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
6
Fiscal Year
2008
Total Cost
$290,367
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
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
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
Guo, Yue-Xian; Li, De-Pei; Chen, Shao-Rui et al. (2013) Distinct intrinsic and synaptic properties of pre-sympathetic and pre-parasympathetic output neurons in Barrington's nucleus. J Neurochem 126:338-48
Cao, Xue-Hong; Chen, Shao-Rui; Li, Li et al. (2012) Nerve injury increases brain-derived neurotrophic factor levels to suppress BK channel activity in primary sensory neurons. J Neurochem 121:944-53
Li, De-Pei; Byan, Hee Sun; Pan, Hui-Lin (2012) Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci 32:372-80
Li, Li; Cao, Xue-Hong; Chen, Shao-Rui et al. (2012) Up-regulation of Cav?3 subunit in primary sensory neurons increases voltage-activated Ca2+ channel activity and nociceptive input in neuropathic pain. J Biol Chem 287:6002-13
Zhou, Hong-Yi; Chen, Shao-Rui; Byun, Hee-Sun et al. (2012) N-methyl-D-aspartate receptor- and calpain-mediated proteolytic cleavage of K+-Cl- cotransporter-2 impairs spinal chloride homeostasis in neuropathic pain. J Biol Chem 287:33853-64
Zhao, Yi-Lin; Chen, Shao-Rui; Chen, Hong et al. (2012) Chronic opioid potentiates presynaptic but impairs postsynaptic N-methyl-D-aspartic acid receptor activity in spinal cords: implications for opioid hyperalgesia and tolerance. J Biol Chem 287:25073-85
Chen, Shao-Rui; Chen, Hong; Yuan, Wei-Xiu et al. (2011) Increased presynaptic and postsynaptic ?2-adrenoceptor activity in the spinal dorsal horn in painful diabetic neuropathy. J Pharmacol Exp Ther 337:285-92

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