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.

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
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
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
Yowtak, June; Lee, Kwan Yeop; Kim, Hee Young et al. (2011) Reactive oxygen species contribute to neuropathic pain by reducing spinal GABA release. Pain 152:844-52
Kim, Jae Hyo; Kim, Hee Young; Chung, Kyungsoon et al. (2011) Electroacupuncture reduces the evoked responses of the spinal dorsal horn neurons in ankle-sprained rats. J Neurophysiol 105:2050-7
Kim, Jae Hyo; Kim, Hee Young; Chung, Kyungsoon et al. (2011) Responses of spinal dorsal horn neurons to foot movements in rats with a sprained ankle. J Neurophysiol 105:2043-9
Kim, Hee Young; Lee, Kwan Yeop; Lu, Ying et al. (2011) Mitochondrial Ca(2+) uptake is essential for synaptic plasticity in pain. J Neurosci 31:12982-91
Lee, Kwan Yeop; Chung, Kyungsoon; Chung, Jin Mo (2010) Involvement of reactive oxygen species in long-term potentiation in the spinal cord dorsal horn. J Neurophysiol 103:382-91
Kim, Hee Young; Koo, Sung Tae; Kim, Jae Hyo et al. (2010) Electroacupuncture analgesia in rat ankle sprain pain model: neural mechanisms. Neurol Res 32 Suppl 1:10-7
Kim, Hee Young; Wang, Jigong; Lu, Ying et al. (2009) Superoxide signaling in pain is independent of nitric oxide signaling. Neuroreport 20:1424-8
Schwartz, Erica S; Kim, Hee Young; Wang, Jigong et al. (2009) Persistent pain is dependent on spinal mitochondrial antioxidant levels. J Neurosci 29:159-68
Boroujerdi, Amin; Kim, Hee Kee; Lyu, Yeoung Su et al. (2008) Injury discharges regulate calcium channel alpha-2-delta-1 subunit upregulation in the dorsal horn that contributes to initiation of neuropathic pain. Pain 139:358-66

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