title: Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury.
abstract: Chronic central neuropathic pain after central nervous system injuries remains refractory to therapeutic interventions. A novel approach would be to target key intracellular signaling proteins that are known to contribute to continued activation by phosphorylation of kinases, transcription factors, and/or receptors that contribute to changes in membrane excitability. We demonstrate that one signaling kinase, calcium/calmodulin-dependent kinase II (CaMKII), is critical in maintaining aberrant dorsal horn neuron hyperexcitability in the neuropathic pain condition after spinal cord injury (SCI). After contusion SCI at spinal level T10, activated CaMKII (phosphorylated, pCaMKII) expression is significantly upregulated in the T7/8 spinal dorsal horn in neurons, but not glial cells, and in oligodendrocytes in the dorsal column in the same rats that displayed at-level mechanical allodynia. Furthermore, identified spinothalamic neurons demonstrated significant increases of pCaMKII after SCI compared to sham-treated control animals. However, neither astrocytes nor microglia showed pCaMKII expression in either sham-treated or SCI rats. To demonstrate causality, treatment of SCI rats with KN-93, which prevents CaMKII activation, significantly attenuated at-level mechanical allodynia and aberrant wide dynamic range neuronal activity evoked by brush, pressure, and pinch stimuli and a graded series of von Frey stimuli, respectively. Persistent CaMKII activation contributes to chronic central neuropathic pain by mechanisms that involve maintained hyperexcitability of wide dynamic range dorsal horn neurons. Furthermore, targeting key signaling proteins is a novel, useful therapeutic strategy for treating chronic central neuropathic pain.
authors.affiliation: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555-1043, USA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Crown
authors.forename: Young S
authors.initials: YS
authors.lastname: Gwak
authors.forename: Zaiming
authors.initials: Z
authors.lastname: Ye
authors.forename: Huai
authors.initials: H
authors.lastname: Yu Tan
authors.forename: Kathia M
authors.initials: KM
authors.lastname: Johnson
authors.forename: Guo-Ying
authors.initials: GY
authors.lastname: Xu
authors.forename: David J
authors.initials: DJ
authors.lastname: McAdoo
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hulsebosch
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D039481:CD11b Antigen / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D009437:Neuralgia / Q000201:enzymology* / Q000209:etiology*; D010147:Pain Measurement; D020671:Posterior Horn Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000150:complications*; D013266:Stilbamidines; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D039481:CD11b Antigen; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D013266:Stilbamidines; D013449:Sulfonamides; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C072105:KN 93; D000096926:Benzenesulfonamides