Abstract
The increase of cytosolic free Ca(2+) ([Ca(2+)](c)) due to NMDA receptor activation is a key step for spinal cord synaptic plasticity by altering cellular signal transduction pathways. We focus on this plasticity as a cause of persistent pain. To provide a mechanism for these classic findings, we report that [Ca(2+)](c) does not trigger synaptic plasticity directly but must first enter into mitochondria. Interfering with mitochondrial Ca(2+) uptake during a [Ca(2+)](c) increase blocks induction of behavioral hyperalgesia and accompanying downstream cell signaling, with reduction of spinal long-term potentiation (LTP). Furthermore, reducing the accompanying mitochondrial superoxide levels lessens hyperalgesia and LTP induction. These results indicate that [Ca(2+)](c) requires downstream mitochondrial Ca(2+) uptake with consequent production of reactive oxygen species (ROS) for synaptic plasticity underlying chronic pain. These results suggest modifying mitochondrial Ca(2+) uptake and thus ROS as a type of chronic pain therapy that should also have broader biologic significance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Calcium / metabolism*
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Calcium Signaling / physiology*
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Cyclic AMP-Dependent Protein Kinases / metabolism
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DNA-Binding Proteins
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Electrophysiological Phenomena
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Hyperalgesia / chemically induced
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Hyperalgesia / physiopathology
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Immunohistochemistry
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Injections, Spinal
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Long-Term Potentiation / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondria / metabolism*
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / metabolism
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Neuronal Plasticity / physiology*
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Nuclear Proteins / metabolism
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Pain / physiopathology*
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Patch-Clamp Techniques
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Protein Kinase C / metabolism
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Receptors, N-Methyl-D-Aspartate / physiology
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Spinal Cord / drug effects
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Superoxides / metabolism
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Synapses / physiology*
Substances
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DNA-Binding Proteins
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Nerve Tissue Proteins
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NeuN protein, mouse
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Nuclear Proteins
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Receptors, N-Methyl-D-Aspartate
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Superoxides
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N-Methylaspartate
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Cyclic AMP-Dependent Protein Kinases
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Protein Kinase C
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Extracellular Signal-Regulated MAP Kinases
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Calcium