Research Summary
Prolonged noxious stimulation initiates a series of LTP-like events leading to increased output of spinal cord sensory neurons to a defined stimulus, this is called spinal sensitization. Although NMDA receptors, a glutamate receptor subtype, have been strongly associated with this process, several clinically relevant models of spinal sensitization appear to involve an alternative subtype called calcium permeable AMPA receptors. My lab is using behavioral pharmacology, Western blots, kinase activity assays and immunohistochemistry to try to differentiate some of the downstream signal transduction cascades that occur subsequent to activation of each of these pathways.
In a different line of work, we have developed a new animal pain model in based on the administration of an antibody to the GD2 ganglioside, which is part of an immunotherapy being used to treat pediatric neuroblastoma. In children and rats the antibody causes a relatively morphine resistant, whole body pain. In rats, we went on to demonstrate with single fiber recording that isolated peripheral nerve fibers develop spontaneous activity and lowered mechanical thresholds following exposure to the antibody, these effects are reversed by low dose systemic lidocaine. Both rats and children have pain relief with lidocaine and with gabapentin. We are now looking at a new antibody with a point mutation that is less effective in activating complement, in rats this agent also causes substantially less pain behavior.
Experiments are underway to determine is activation of the complement cascade is in fact the major source of the pain in these animals. Pain behavior and axonal electrophysiological changes are mimicked by local administration of the pro-inflammatory cytokine TNFα to the nerve trunk or the dorsal root ganglia (DGR). We have gone on to show that TNFα is a major contributor to neuropathic pain both at the level of the DRG and the spinal cord, in part, through its activation of the MAP kinase p38. We are presently examining activators in between TNF and p38, at both of these loci, to help delineate the signal transduction process by which injury leads to MAP kinase activation, to determine if the pathway differs according to cell type and to help discern better pharmacological targets for pain control.
Publications
Sorkin, L.S., et al., Spinal adenosine agonist reduces c-fos and astrocyte activation in dorsal horn of rats with adjuvant-induced arthritis. Neurosci Lett, 2003. 340(2): p. 119-22.
Schafers, M., et al., Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve ligation. J Neurosci, 2003. 23(7): p. 3028-38.
Schafers, M., et al., Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci, 2003. 23(7): p. 2517-21.
Jones, T.L. and L.S. Sorkin, Calcium-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors mediate development, but not maintenance, of secondary allodynia evoked by first-degree burn in the rat. J Pharmacol Exp Ther, 2004. 310(1): p. 223-9.
Svensson, C.I., et al., Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett, 2005. 379(3): p. 209-13.
Jones, T.L. and L.S. Sorkin, Activated PKA and PKC, but not CaMKIIalpha, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain, 2005. 117(3): p. 259-70.
