Yaksh Research Lab Faculty

Dr. Tony Yaksh 

Tony Yaksh Research Summary

The goal of my work is to understand the encoding process for nociceptive information to permit development of pharmacological therapies for the management of pain. My current work follows along three lines.

Pharmacology of afferent & spinal systems which process nociceptive information

A facilitated state of processing occurs with tissue and nerve injury. We have shown that these facilitated states reflect complex spinal cascades in which afferent transmitters activate downstream MAPKs which though PLA2 and COX 2 isozymes initiate spinal synthesis and release of a variety of lipidic acid mediators.

These studies have also emphasized the significance of microglia in this organization. As shown below, there is a low level of activated (phosphorylated) p38 MAPK in spinal dorsal horn following spinal injection of saline (A). Intrathecal substance P activates p38 MAPK in the spinal dorsal horn(B). The phosphorylated p38 MAPK colocalizes with microglia (D) but not with neurons(C). Using intrathecal antagonists and antisense, we showed that block of P38&beta isoform, located in microglia, is potently anti-hyperalgesic.

Background

  • Ph.D. from Purdue (1971)
  • U.S. Army, Biomedical Laboratory at Edgewood Arsenal, MD (1971-73)
  • Research scientist in the School of Pharmacy, University of Wisconsin (1973-76)
  • Associate Research Scientist in Anatomy Department, University College London (1976-77)
  • Professor in Pharmacology and Neurosurgery, Mayo Clinic Rocester (1977-1988)
  • Distinguished Professor in Anesthesiology and Pharmacology and Vice Chairman for Research in Anesthesiology(1988-present)
  • Co-director of the Pain and Symptom Management Core of the UCSD Regional Cancer Center
Dr. Yaksh has been funded consistently by the NIH since 1977 and has been a mentor to more than 100 post-graduate Fellows. He has received several awards,including the FWL Kerr Award of the American Pain Society, Peter W. Lampert Memorial Lecturer, Academy of Pain Medicine, Award for Outstanding Contributions to Pain Medicine, and the American Society of Anesthesiology (ASA) Annual Award for Excellence in Research. He has published over 600 papers to date.

Linda Sorkin Research Summary

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.

Background

  • B.S. in Psychobiology(1975) and Ph.D.in Psychobiology (1983), University of Michigan
  • Post-doctoral fellowships
    - Bill Willis, University of Texas Medical Branch (UTMB), Galveston
    - Fernando Cervero, Bristol University, United Kingdom
  • Research Associate at UTMB (1987-91)
  • Assistant Professor, then Professor in Anesthesiology and member of the Neurosciences Group (1991- present)

Dr. Sorkin is a past member of the board of directors of the American Pain Society and the research committee of the International Society for the Study of Pain. She currently serves on the editorial board for the journals Pain and The Journal of Pain and is the pain mechanisms section editor for the journal, Neuroscience.

Dr. Xiao-Ying Hua

Xiao-Ying Hua Research Summary

My major research interests include (1) investigation of role of selective protein  kinases including protein kinase C (PKCα isoform) and mitogen-activated protein kinases (P38α, P38β) in spinal pain transmission by using intrathecal antisense approach; (2) study of activation and regulation of these protein kinases at spinal level during tissue injury/inflammation and development of morphine tolerance; and (3) participation of non-neuronal cells, such as microglia and astrocytes, in spinal hyperexcitability. 

Selected Publications

Hua, X.-Y., A. Moore, S. Malkmus, S.F. Murray, N. Dean, T.L. Yaksh & M. Butler. Inhibition of spinal protein kinase C alpha expression by an antisense oligonucleotide attenuates morphine infusion-induced tolerance. Neuroscience, 113:99-107, 2002.

Svensson C.I., X.-Y. Hua, A.A. Protter, H.C. Powell & T.L. Yaksh. Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE2 release and thermal hyperalgesia. Neuroreport 14:1153-1157, 2003.

Butler, M., C.S. Hayes, A. Chappel, S.F. Murray, T.L. Yaksh & X-Y Hua. Spinal distribution and metabolism of 2'-O-(2-Methoxyethyl)-modified oligonucleotides after intrathecal administration in rats. Neuroscience 131: 705-714, 2005.

Svensson C.I., B. Fitzmmons, S. Azizi, H.C. Powell, X.-Y. Hua, & T.L. Yaksh. Spinal p38β isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J. Neurochem. 92:1508-1520, 2005.

Svensson, C.I., X.-Y. Hua, H.C. Powell, E.A. J. Lai, F. Porreca & T.L. Yaksh. Prostaglandin E2 release evoked by intrathecal dynorphin is dependent on spinal p38 mitogen activated protein kinase. Neuropeptides, 39: 485-494, 2005.

Hua, X.-Y., C.I. Svensson, T. Matsui, B. Fitzmmons, T.L. Yaksh & M. Webb. Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia. Eur J Neurosci, 22: 2431-2440, 2005.

Background

  • M.D. from Capital University of Medical Science, Beijing, China (1977)
  • Ph.D. from Karolinska Institute, Stockholm, Sweden (1986)
  • Research Scientist, Anesthesiology, University California San Diego (1989- present)

Martin Marsala Research Summary

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