Reactive oxygen species involvement in gabaergic dysfunction in neuropathic pain

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dc.contributor.advisorJin Mo Chung, PhDen_US
dc.contributor.committeeMemberWilliam D. Willis, MD, PhDen_US
dc.contributor.committeeMemberShawn D. Newlands, MD, PhDen_US
dc.contributor.committeeMemberLinda S. Sorkin, PhDen_US
dc.contributor.committeeMemberKyungsoon Chung, PhDen_US
dc.contributor.committeeMemberJoel P. Gallagher, PhDen_US
dc.creatorJune Yowtaken_US
dc.date.accessioned2011-12-20T16:05:12Z
dc.date.available2010-09-28en_US
dc.date.available2011-12-20T16:05:12Z
dc.date.created2008-08-20en_US
dc.date.issued2008-06-18en_US
dc.description.abstractNeuropathic pain caused by peripheral nerve damage results in ectopic neuronal excitability, primary sensory neuron degeneration, loss of inhibition by spinal GABAergic neurons and more importantly, the development of central sensitization—increased sensitivity of dorsal horn neurons to stimuli. Oxidative stress due to excessive levels of reactive oxygen species (ROS) has been implicated in the development and maintenance of neuropathic pain. However, it is not known whether oxidative stress is related to the loss of GABAergic tone in the spinal cord. Therefore, the major goal of this work was to elucidate the effects of ROS on GABAergic neuron function and expression.\r\n\r\nThe spinal nerve ligation model (SNL) served as a useful paradigm to study chronic neuropathic pain. SNL mice were produced by tight ligation of the L5 spinal nerve, resulting in increased pain behaviors lasting for many weeks. The paw withdrawal response rates to von Frey filaments measured pain behaviors in the form of mechanical allodynia. Scavenging ROS or increasing spinal GABA neurotransmission produced analgesia in the SNL model. On the other hand, increasing spinal ROS levels or reducing GABA neurotransmission temporarily induced pain behaviors in normal mice. Field recordings demonstrated that the spinal cord dorsal horn neurons were sensitized in SNL mice, and scavenging ROS reduced central sensitization. Blocking GABA neurotransmission significantly reduced this desensitization, indicating that ROS acted mainly upstream to postsynaptic, spinal GABA receptors. Whole cell recordings revealed that elevated levels of ROS increased dorsal horn neuronal excitability but also reduced GABA neuronal excitability. This suggested that ROS may directly contribute to reduced GABA function. Stereological analysis demonstrated that the number of fluorescently tagged GAD67-containing (GABA) neurons is reduced after SNL in the affected spinal dorsal horn. Furthermore, treatment with a ROS scavenger significantly reduced the magnitude of the allodynic behaviors and the SNL-induced loss of GAD67 expression. Therefore, the loss of spinal GABAergic inhibition seen in neuropathic pain may be partly attributed to oxidative stress reducing GABA neuron excitability and promoting the loss of GAD67-producing neurons or down-regulating GAD67 expression. Overall, these studies suggest that ROS play an important role in GABAergic dysfunction that contributes to neuropathic pain.\r\nen_US
dc.format.mediumelectronicen_US
dc.identifier.otheretd-08202008-181344en_US
dc.identifier.urihttp://hdl.handle.net/2152.3/213
dc.language.isoengen_US
dc.rightsCopyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.en_US
dc.subjectROSen_US
dc.subjectreactive oxygen speciesen_US
dc.subjectpainen_US
dc.subjectoxidative stressen_US
dc.subjectneuropathicen_US
dc.subjectGABAen_US
dc.titleReactive oxygen species involvement in gabaergic dysfunction in neuropathic painen_US
dc.type.genredissertationen_US
dc.type.materialtexten_US
thesis.degree.departmentNeuroscienceen_US
thesis.degree.grantorThe University of Texas Medical Branchen_US
thesis.degree.levelDoctoralen_US
thesis.degree.namePhDen_US

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