Linda S. Sorkin, Ph.D.
University of California, San Diego
firstname.lastname@example.org 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 developed a new animal pain model 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, as in rats this agent also causes substantially less pain behavior.
We have sought to determine if activation of the complement cascade is 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.
More recently we have begun to address signaling cascades that are relevant to tissue injury and inflammation to event relevant to the trigeminal systems, notably those mechanisms leading to migraine.
BS: Psychobiology, 1975, University Of Michigan
PhD: Psychobiology, 1983, University Of Michigan
Postdoc Fellow: 1983-85, Univ. of Texas Medical Branch (UTMB), Galveston, TX, with Professor Bill Willis
Postdoc Fellow: 1985-86, Briston University, UK, with Professor Fernando Cervero
1987-1991: Research Associate, UTMB, Galveston, TX
1991 1995: Assistant Professor, Department of Anesthesiology, UC San Diego, La Jolla, CA
1995 2000: Associate Professor, Department of Anesthesiology, UC San Diego, La Jolla, CA
2000-Present: Professor, Department of Anesthesiology, UC San Diego, La Jolla, CA
SELECTED PUBLICATIONS (Selected from 91)
- Sorkin LS, Eddinger KA, Woller SA, Yaksh TL.Origins of antidromic activity in sensory afferent fibers and neurogenic inflammation.Semin Immunopathol. 2018 May;40(3):237-247.
- Wigerblad G, Huie JR, Yin HZ, Leinders M, Pritchard RA, Koehrn FJ, Xiao WH, Bennett GJ, Huganir RL, Ferguson AR, Weiss JH, Svensson CI, Sorkin LS AprInflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A..Exp Neurol. 2017 Jul;293:144-158.
- Leinders M, Üçeyler N, Pritchard RA, Sommer C, Sorkin LS.Increased miR-132-3p expression is associated with chronic neuropathic pain.Exp Neurol. 2016 Sep;283(Pt A):276-86.
- Sikandar S, Gustavsson Y, Marino MJ, Dickenson AH, Yaksh TL, Sorkin LS, Ramachandran R.Effects of intraplantar botulinum toxin-B on carrageenan-induced changes in nociception and spinal phosphorylation of GluA1 and Akt.Eur J Neurosci. 2016 Jul;44(1):1714-22.
- Yaksh TL, Woller SA, Ramachandran R, Sorkin LS. The search for novel analgesics: targets and mechanisms. F1000Prime Rep. 2015 May 26;7:56.