Reactive oxygen species involvement in gabaergic dysfunction in neuropathic pain



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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



ROS, reactive oxygen species, pain, oxidative stress, neuropathic, GABA