Linda Sorkin, PhD

Linda Sorkin, PhD

Professor

 

Contact Information

Office: 307 CTF-C
Lab: 619-543-3498
Fax: 619-543-6070
Email: lsorkin@ucsd.edu  

Experiments in my lab are focused on understanding the pharmacological changes in the spinal cord following peripheral injury which give rise to altered sensory processing in the spinal dorsal horn such that 1) painful or nociceptive input is enhanced and 2) low threshold cutaneous input activates nociceptive pathways and is perceived as pain. Recently, projects have included looking at different insults to the peripheral nerve that give rise to such alterations; specifically the sequelae of local immune system challenge to the nerve resulting in pain.

A Role for Ca2+ Permeable AMPA Receptors in Spinal Sensitization.
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. Importantly, 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 AMPA receptor antagonists also blocks pain behavior. We have recently shown that following peripheral inflammation, Ca2+ permeable AMPA receptors are inserted into neuronal membranes in the dorsal horn. One trigger for this is spinal release of tumor necrosis factor (TNF). We are in the midst of working out the multistep pathway between TNF actions on its receptor and AMPA receptor phosphorylation and insertion. Immunohistochemistry and confocal analysis has documented that neurons in different laminae of the dorsal horn exhibit activation of particular enzymes such as Akt as much as an hour apart during this process and we are trying to figure out the wiring of the respective responses.

Immune System Activation of Peripheral Nociceptive Nerve Fibers.
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 and neurontin in blocking pain behavior and ectopic activity. We are working with variants of the antibody with point mutations that affect its ability to activate compliment to determine how much of this pain behavior (most of it) is due to complement activation and which complement fractions are involved in the different phases of the behavior.

Sorkin, L.S., Yaksh, T.L., and Doom, C.M. Pain models display differential sensitivity to Ca2+- permeable non-NMDA glutamate receptor antagonists. Anesthesiology 95: 965-73, 2001.

Schäfers, M., Svensson, C.I., Sommer, C., and Sorkin, L.S. Tumor necrosis factor-? induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23:2517-2521, 2003.

Schaefers, 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-Ą after spinal nerve ligation. J. Neurosci. 23:3028-3038, 2003.

Schaefers, M., Sorkin, L.S., Geis, C., and Shubayev, V.I. Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci. Lett. 347:179-182, 2003.

Pogatzki, E.M., Niemeier, J.S., Sorkin, L.S., and Brennan, T.J. Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 105:97-107, 2003.

Schäfers, M., Sorkin, L.S., and Sommer, C. Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain 104: 579-588, 2003.

Sorkin, L.S., Moore, J., Boyle, D.L., Yang, L., and Firestein, G.S. Regulation of peripheral inflammation by spinal adenosine: role of somatic afferent fibers. Exper. Neurol. 184: 162-168, 2003.

Jones, T.L., and Sorkin, L.S. Calcium-permeable ?-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. 310:223-229, 2004.

Schäfers, M., Svensson, C.I., Sommer, C., and Sorkin, L.S. Tumor necrosis factor-± induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J. Neurosci. 23:2517-2521, 2003.

Schäfers, 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.

Schäfers, M., Sorkin, L.S., Geis, C., and Shubayev, V.I. Spinal nerve ligation induces transient upregulation of tumor necrosis factor receptors 1 and 2 in injured and adjacent uninjured dorsal root ganglia in the rat. Neurosci. Lett. 347: 179-182, 2003.

Schäfers, M., Sorkin, L.S., and Sommer, C. Intramuscular injection of tumor necrosis factor-alpha induces muscle hyperalgesia in rats. Pain. 104: 579-588, 2003.

Jones, T.L., and Sorkin, L.S. Calcium-permeable ±-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: 223-229, 2004.

Svensson, C.I., Schafers, M., Jones, T.L., Powell, H., Sorkin, L.S. Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci. Lett. 379 :209-213, 2005.

Jones, T.L., and Sorkin L.S. Activated PKA and PKC, but not CaMKII alpha, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain. 117: 259-270, 2005.

Svensson, C.I., Schafers, M., Jones, T.L., Yaksh, T.L. and Sorkin, L.S. Co-variance among age, spinal p38 MAP kinase activation and allodynia. J.Pain 7: 337-345, 2006

Boyle, D.L., Jones, T.L., Hammaker, D. Svensson, C.I., Albani, S., Sorkin, L.S., Firestein, G.S. Regulation of peripheral inflammation by Spinal p38 MAP Kinase in Rats. PLOS Medicine plosmedicine.org ePub 338 September 3(9), 2006.

Jones, T.L., Hefferan, M.P., Marsala, M., Sorkin, L.S. Low-speed subcellular fractionation method for determining noxious stimulus-evoked spinal neurokinin-1 receptor internalization. Journal of Neuroscience Methods 161: 23-31, 2007

Schaefers, M., Sorkin, L.S. Effect of cytokines on neuronal excitability. Neurosci. Lett. 437:188-193, 2008.

Schaefers, M., Sommer, C., Geis, C., Hagenacker, T., Vansenabeele, P., Sorkin, L.S. Selective stimulation of either tumor necrosis factor receptor differentially Induces pain behavior in vivo and ectopic activity in sensory neurons in vitro. Neurosci. 157:414-423, 2008.

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. 87:948-955, 2009.

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. 162:462-471, 2009.