Results of research lab:
- Prolonged noxious stimulation initiates a series of events leading to spinal sensitization
- This results in increased responsivity of spinal neurons to a given stimulus, neuronal recruitment and enhanced pain behavior
- Studies over the last 10 years indicate that an amino acid receptor subtype, the NMDAr, is responsible
- In many pain models, intrathecal (i.t.) pretreatment with NMDAr antagonists blocks development of enhanced pain behavior
- In other manifestations, such as MAP kinase phosphorylation or expression of c-fos, the enhanced response is only partially reduced by the same antagonist pretreatment
- It is now thought that multiple pathways contribute to spinal sensitization, even in models where NMDAr antagonists are sufficient to block pain behavior
- Experiments in my lab show that intrathecal pretreatment with Ca2+ permeable non-NMDA receptor antagonists is also effective
- We are now exploring the idea that spinal release of tumor necrosis factor (TNF) possibly released from local glia causes trafficking of glutamate receptors from the membrane to the cytosol and back resulting in an upregulation of Ca2+ permeable AMPA receptors in some pain states
- 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
- We developed an animal model of that pain, measured as mechanical sensitivity, 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 in blocking pain behavior and ectopic activity
- Appears to be due in large part to the ability of the antibody to fix complement
- Pain behavior in the rat and axonal electrophysiological changes are mimicked by local administration of TNFa to the nerve trunk or into the dorsal root ganglion (DRGs)
- Have gone on to show that TNF is a major contributor to neuropathic pain
- Antagonism of TNF leads to reduction of pain behavior as does antagonism of p38 MAP kinase activity
- Nerve injury elicits an increase in p38 activation in both the relevant DRGs and spinal cord
- We are exploring the signal transduction pathway by which TNF activates p38 in both neurons (DRG) and microglia (spinal cord)
Jones TL, Hefferan MP, Marsala M, Sorkin LS Low-speed subcellular fractionation method for determining noxious stimulus-evoked spinal neurokinin-1 receptor internalization. J Neurosci Meths 161:23-31, 2007.
Boyle DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, Albani S, Sorkin L, Firestein GS. Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 3 e338, 2006.
Jones TL, Sorkin LS. Activated PKA and PKC, but not CaMKIIalpha, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain 117:259-270, 2005.
Jones TL, Sorkin LS. 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.;310:223-9, 2004.
Schaafers M, Marziniak M, Sorkin LS, Yaksh TL, Sommer C. Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in the rat.Exp Neurol. 2004 Jan;185:160-8
Schäfers, M., Svensson, C.I., Sommer, C., and Sorkin, L.S. Tumor necrosis factor-a induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23: 2517-2521, 2003.
Schafers, M., Lee, D.H., Brors, D., Yaksh, T.L., and Sorkin, L.S. Increased sensitivity of injured and adjacent uninjured rat primary sensory neurons to exogenous tumor necrosis factor- after spinal nerve ligation. J. Neurosci. 23:3028-3038, 2003.
Schafers, M., Sorkin, L.S., and Sommer, C. Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain. 104: 579-588, 2003.