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1.
Ann Neurol ; 59(5): 843-51, 2006 May.
Article in English | MEDLINE | ID: mdl-16634039

ABSTRACT

OBJECTIVE: Our objective was to elucidate the mechanisms responsible for below-level pain after partial spinal cord injury (SCI). METHODS: We used lateral hemisection to model central neuropathic pain and herpes simplex viral (HSV) vector-mediated transfer of the cleaved soluble receptor for tumor necrosis factor-alpha (TNF-alpha) to evaluate the role of TNF-alpha in the pathogenesis of below-level pain. RESULTS: We found activation of microglia and increased expression of TNF-alpha below the level of the lesion in the lumbar spinal cord after T13 lateral hemisection that correlated with emergence of mechanical allodynia in the hind limbs of rats. Lumbar TNF-alpha had an apparent molecular weight of 27 kDa, consistent with the full-length transmembrane form of the protein (mTNF-alpha). Expression of the p55 TNF soluble receptor (sTNFRs) by HSV-mediated gene transfer resulted in reduced pain behavior and a decreased number of ED1-positive cells, as well as decreased phosphorylation of the p38 MAP kinase (p-p38) and diminished expression of mTNF-alpha in the dorsal horn. INTERPRETATION: These results suggest that expression of mTNF-alpha after injury is related to development of pain, and that reverse signaling through mTNF-alpha by sTNFR at that level reduces cellular markers of inflammatory response and pain-related behavior.


Subject(s)
Pain/etiology , Pain/physiopathology , Spinal Cord Injuries/complications , Tumor Necrosis Factor-alpha/physiology , Animals , Blotting, Western , Enzyme-Linked Immunosorbent Assay , Female , Genetic Vectors , Immunohistochemistry , Microglia , Rats , Rats, Sprague-Dawley , Receptors, Tumor Necrosis Factor, Type I/genetics , Simplexvirus/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
2.
Brain Res ; 1073-1074: 297-304, 2006 Feb 16.
Article in English | MEDLINE | ID: mdl-16460707

ABSTRACT

We have demonstrated that dorsal root ganglion neurons transduced with a recombinant replication-defective herpes simplex virus vector coding for glutamic acid decarboxylase (QHGAD67) release GABA to produce an analgesic effect in rodent models of pain. In this study, we examined the mechanism of transgene-mediated GABA release from dorsal root ganglion neurons in vitro and in vivo. Release of GABA from dorsal root ganglion neurons transduced with QHGAD67 was not increased by membrane depolarization induced by 60 mM extracellular K+ nor reduced by the removal of Ca2+ from the medium. Release of GABA from transduced dorsal root ganglion neurons was, however, blocked in a dose-dependent manner by NO-711, a selective inhibitor of the GABA transporter-1. The amount of GABA released from a spinal cord slice preparation, prepared from animals transduced by subcutaneous inoculation of QHGAD67 in the hind paws, was substantially increased compared to animals transduced with control vector Q0ZHG or normal animals, but the amount of GABA released was not changed by stimulation of the dorsal roots at either low (0.1 mA, 0.5-ms duration) or high (10 mA, 0.5-ms duration) intensity. We conclude that QHGAD67-mediated GABA release from dorsal root ganglion neurons is non-vesicular, independent of electrical depolarization, and that this efflux is mediated through reversal of the GABA transporter.


Subject(s)
Glutamate Decarboxylase/metabolism , Isoenzymes/metabolism , Neurons, Afferent/metabolism , gamma-Aminobutyric Acid/metabolism , Analysis of Variance , Animals , Cells, Cultured , Chromatography, High Pressure Liquid/methods , Dizocilpine Maleate/pharmacology , Dose-Response Relationship, Radiation , Drug Interactions , Electric Stimulation/methods , Embryo, Mammalian , Excitatory Amino Acid Antagonists/pharmacology , GABA Antagonists/pharmacology , Ganglia, Spinal/cytology , Glutamate Decarboxylase/genetics , Glutamate Decarboxylase/immunology , Glutamic Acid/pharmacology , Glutamine/analogs & derivatives , Glutamine/pharmacology , Isoenzymes/genetics , Isoenzymes/immunology , Neurons, Afferent/virology , Nipecotic Acids/pharmacology , Oximes/pharmacology , Rats , Rats, Sprague-Dawley , Simplexvirus/genetics , Spinal Nerves/physiology , Spinal Nerves/radiation effects , Transfection/methods , Tubulin/metabolism
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