kn-93 and Spinal-Cord-Injuries

In the present study, we examined superoxide-mediated excitatory nociceptive transmission on at-level neuropathic pain following spinal thoracic 10 contusion injury (SCI) in male Sprague Dawley rats.. Mechanical sensitivity at body trunk, neuronal firing activity, and expression of superoxide marker/ionotropic glutamate receptors (iGluRs)/CamKII were measured in the T7/8 dorsal horn, respectively.. Topical treatment of superoxide donor t-BOOH (0.4 mg/kg) increased neuronal firing rates and pCamKII expression in the naïve group, whereas superoxide scavenger Tempol (1 mg/kg) and non-specific ROS scavenger PBN (3 mg/kg) decreased firing rates in the SCI group (*. Superoxide and the pCamKII pathway contribute to chronic at-level neuropathic pain without involvement of iGluRs following SCI.

Topics: Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Contusions; Cyclic N-Oxides; Free Radical Scavengers; Hyperalgesia; Male; Models, Animal; Nerve Tissue Proteins; Neuralgia; Nociception; Pain Threshold; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, Ionotropic Glutamate; Spin Labels; Spinal Cord Dorsal Horn; Spinal Cord Injuries; Sulfonamides; Superoxides; Synaptic Transmission

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.

Topics: Action Potentials; Analysis of Variance; Animals; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; CD11b Antigen; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Neuralgia; Pain Measurement; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Cord Injuries; Stilbamidines; Sulfonamides; Time Factors