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My group has two main foci. We are now exploring the idea that spinal release of tumor necrosis factor (TNF) released from local glia causes trafficking of the AMPA subtype of glutamate receptor from the membrane to the cytosol resulting in increased density of functional AMPA receptors in the membrane of equal or perhaps more importance, a significant percentage of these newly incorporated AMPA receptors are permeable to Ca2+ and participate in synaptic strengthening and sensitization. As NMDA receptor activation can also cause increased insertion of AMPA receptors into the membrane, we are looking at the complete signal transduction cascades initiated by activation of these 2 receptors (TNF and NMDA) to determine the points at which they converge and where they employ different mechanisms. To do so we are using behavior, Western blots and a series of anatomical techniques including confocal microscopy, electron microscopy and cobalt staining in dorsal horn explants.
In a different line of research, we learned that antibody to a specific ganglioside (GD2) that is being administered to pediatric neuroblastoma patients at UCSD caused a relatively morphine resistant pain. This pain state includes a whole body dynamic allodynia and constant spontaneous visceral pain. We developed an animal model of the touch evoked pain and have demonstrated with single fiber recording that isolated peripheral nerve fibers develop spontaneous activity and lowered mechanical thresholds following exposure to the antibody. Both rats and children have beneficial effects of low dose systemic lidocaine and gabapentin in blocking pain behavior and ectopic activity. This appears to be due in large part to the ability of the antibody to fix complement and activate complement receptor 5a as well as to generate membrane attack complex. We are starting a series of experiments to develop a GD2 antibody model of visceral pain and to determine if the therapeutic agents that are effective in blocking the cutaneous pain are equally effective in stopping the spontaneous visceral pain.
Publications (Selected From 125 Publications)
Schafers, M., Sommer, C., Geis, C., Hagenacker, T., Vandenabeele, P., Sorkin, L.S. Selective stimulations of either tumor necrosis factor receptor differentially induces pain behavior in vivo and ectopic activity in sensory neurons in vitro. Neurosci., 157(2):414-23, 2008.
Sorkin, L.S., Boyle, D.L., Hammaker, D., Herman, D.S., Vail, E., Firestein, G.S. MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice. Neurosci., 162(2):462-71, 2009.
Sorkin, L.S., Svensson, C.I., Jones-Cordero, T.L., Hefferan, M., Campana, W.M. Spinal p38 map kinase mediates allodynia induced by first-degree burn in rat. J. Neurosci. Res., 87(4):948-955, 2009.
Choi, J-I, Svensson, CI, Koehrn, FJ, Bhuskute, A, Sorkin, LS Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking in spinal cord in addition to pain behavior. Pain 149:243-253, 2010.
Sorkin, L. S., Otto, M., Baldwin, W. M., 3rd, Vail, E., Gillies, S. D., Handgretinger, R., Barfield, R. C., Ming Yu, H.,Yu, A. L.Anti-GD2 with an FC point mutation reduces complement fixation and decreases anti-body induced allodynia. Pain, 149:135-142, 2010.