Abstract

An important mechanism underlying neuropathic pain is plastic changes in spinal cord dorsal horn neurons, in that they change sensitivity to peripheral inputs. Such changes include increases or decreases in efficacy of afferent synaptic inputs, often called spinal LTP and LTD (sLTP and sLTD) because these physiological phenomena are similar to the long term potentiation (LTP) and long term depression (LTD) extensively studied in the hippocampus. We hypothesize that nociceptive peripheral input induces sLTP in spinothalamic tract neurons (STTn) but sLTD in GABAergic inhibitory interneurons (GABAn). This cell-type specific synaptic plasticity is mediated by cell-type specific intracellular signaling mechanisms caused by two different free radicals that, in turn, are due to differences in iron content of these different cell types.
Three specific aims test this hypothesis.
Specific aim 1 tests the hypothesis that nociceptive input causes NMDA receptor-mediated intracellular calcium influx which leads to sLTP in STTn but sLTD in GABAn in the spinal cord. Single cell patch recordings will be made from identified STTn (labeled with a retrogradely transported dye) and GABAn (using a transgenic mouse whose GABAn are tagged with green fluorescent protein) in spinal cord slices.
Specific aim 2 is to test the hypothesis that the same nociceptive input to the spinal cord induces sLTP in STTn but sLTD in GABAn because two different intracellular signaling free radicals are involved, superoxide and hydroxyl radical, respectively.
Specific aim 3 is to test the hypothesis that GABAn contain high levels of iron, in turn causing over-production of hydroxyl radicals via superoxide-driven Fenton chemical reactions, and that this over-production then produces sLTD in GABAn. This hypothesis of cell-type and free radical-type specific synaptic plasticity may explain why nerve injuries often lead to chronic neuropathic pain. If proven to be true, this proposal may lead to several avenues for treating chronic neuropathic pain.

Public Health Relevance

This proposal hypothesizes that nociceptive input to the spinal cord induces long term synaptic enhancement in projection neurons but long term synaptic depression in inhibitory interneurons. This dichotomy may explain why nerve injuries often lead to chronic neuropathic pain. If proven to be true, this proposal may lead to several avenues for treating chronic neuropathic pain.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031680-15
Application #
8413612
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Babcock, Debra J
Project Start
1993-12-01
Project End
2017-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
15
Fiscal Year
2013
Total Cost
$322,974
Indirect Cost
$111,880

  Institution

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

  Publications

Bae, Chilman; Wang, Jigong; Shim, Hyun Soo et al. (2018) Mitochondrial superoxide increases excitatory synaptic strength in spinal dorsal horn neurons of neuropathic mice. Mol Pain 14:1744806918797032
La, Jun-Ho; Chung, Jin Mo (2017) Peripheral afferents and spinal inhibitory system in dynamic and static mechanical allodynia. Pain 158:2285-2289
Kim, Do-Hee; Ryu, Yeonhee; Hahm, Dae Hyun et al. (2017) Acupuncture points can be identified as cutaneous neurogenic inflammatory spots. Sci Rep 7:15214
Bittar, Alice; Jun, Jaebeom; La, Jun-Ho et al. (2017) Reactive oxygen species affect spinal cell type-specific synaptic plasticity in a model of neuropathic pain. Pain 158:2137-2146
La, Jun-Ho; Wang, Jigong; Bittar, Alice et al. (2017) Differential involvement of reactive oxygen species in a mouse model of capsaicin-induced secondary mechanical hyperalgesia and allodynia. Mol Pain 13:1744806917713907
Young, E E; Bryant, C D; Lee, S E et al. (2016) Systems genetic and pharmacological analysis identifies candidate genes underlying mechanosensation in the von Frey test. Genes Brain Behav 15:604-15
Shih, Alvin M; Varghese, Lincy; Bittar, Alice et al. (2016) Dysregulation of Norepinephrine Release in the Absence of Functional Synaptotagmin 7. J Cell Biochem 117:1446-53
Kim, Hee Young; Lee, Inhyung; Chun, Sang Woo et al. (2015) Reactive Oxygen Species Donors Increase the Responsiveness of Dorsal Horn Neurons and Induce Mechanical Hyperalgesia in Rats. Neural Plast 2015:293423
Kim, Hee Young; Jun, Jaebeom; Wang, Jigong et al. (2015) Induction of long-term potentiation and long-term depression is cell-type specific in the spinal cord. Pain 156:618-25
Yowtak, June; Wang, Jigong; Kim, Hee Young et al. (2013) Effect of antioxidant treatment on spinal GABA neurons in a neuropathic pain model in the mouse. Pain 154:2469-76

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