Reactive oxygen species involvement in gabaergic dysfunction in neuropathic pain

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Title: Reactive oxygen species involvement in gabaergic dysfunction in neuropathic pain
Author: June Yowtak
Abstract: Neuropathic 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 \n
URI: http : / /hdl .handle .net /2152 .3 /213
Date: 2008-06-18


Reactive oxygen species involvement in gabaergic dysfunction in neuropathic pain. Doctoral dissertation, The University of Texas Medical Branch. Available electronically from http : / /hdl .handle .net /2152 .3 /213 .

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