title: Mitochondrial Ca(2+) uptake is essential for synaptic plasticity in pain.
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.
authors: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas 77555-1069, USA.
authors: Hee Young
authors: HY
authors: Kim
authors: Kwan Yeop
authors: KY
authors: Lee
authors: Ying
authors: Y
authors: Lu
authors: Jigong
authors: J
authors: Wang
authors: Lian
authors: L
authors: Cui
authors: Sang Jeong
authors: SJ
authors: Kim
authors: Jin Mo
authors: JM
authors: Chung
authors: Kyungsoon
authors: K
authors: Chung
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D055724:Electrophysiological Phenomena; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D007150:Immunohistochemistry; D007278:Injections, Spinal; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D010146:Pain / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; D016202:N-Methylaspartate; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium