The overall objective of this proposal, which is a response to the Program Announcement New Directions in Pain Research, is to study the role of peripheral glutamate receptors in the generation of ectopic discharges from injured nerves as it relates to neuropathic pain. Preliminary evidence is presented that glutamate is accumulated at the site of nerve injury and block of ionotropic glutamate receptors decreases ectopic discharges recorded from injured nerve axons and attenuates pain behaviors in a rat model of neuropathic pain. The following hypotheses will be tested: 1. Blockade of ionotropic glutamate receptors or inhibition of glutamate synthesis at the site of nerve injury attenuates neuropathic pain states; 2. Peripheral nerve injury elicits an augmented expression of ionotropic glutamate receptors at the site of nerve injury and an increased glutaminase activity in the neuroma, dorsal root ganglia and spinal cord; 3. Peripheral nerve injury increases local glutamate accumulation, which is attenuated by inhibition of glutaminase or blockade of ionotropic glutamate receptors; and 4. Glutamate accumulation at the site of nerve injury contributes to the generation of abnormal afferent discharges, which play an important role in the sensitization of spinal dorsal horn neurons. A tight partial sciatic nerve ligation rat model of neuropathic pain will be used. Behavioral assessment of allodynia will be threshold to withdrawal using von Frey filaments. Motor function will also be evaluated. Ectopic nerve activity proximal to the ligation will be measured by extracellular recording from split filaments and assigned to fiber class on the basis of conduction velocity. Single unit recording of dorsal horn neural activity will also be done. Immunocytochemistry and electron microscopy will be used to detect changes in glutamate receptor expression, which will also be measured quantitatively by Western blot. Glutamate and aspartate content of nerve samples will be measured with HPLC. Glutaminase will be measured by HPLC determinations of glutamate over time.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Cole, Alison E
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Pennsylvania State University
Schools of Medicine
United States
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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
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
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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