Browsing by Subject "neuropathic pain"
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Item Mechanisms of improvement following functional inhibition of neutrophil infiltration after spinal cord injury(2006-12-06) Michael Wayne Carter; Claire E. Hulsebosch; Judith F. Aronson; Donald S. Prough; David J. McAdoo; Alan R. LightSpinal Cord Injury (SCI) is a traumatic event that results in loss of function below the level of injury, and other dysfunctions including pain syndromes, both above and below the level of the lesion. A cascade of biochemical and cellular events leads to secondary events after SCI, exacerbating the injury, and contributes to loss of tissue and increased dysfunctions. While thought to be beneficial, inflammation induced by trauma in the spinal cord contributes to secondary injury early in SCI. Thus, in this project a mammalian model is used to investigate a targeted anti-inflammatory treatment for SCI, and compare it with the current standard therapy of high dose methylprednisolone (MPSS).\r\nTo ensure that the new generation of devices used in experimental SCI can reliably produce an injury that parallels the outcomes seen in the clinical setting, we characterized a rodent model of SCI by adjusting several mechanical parameters of the device. Injuries with higher force or increased duration of compression increased sensitivity to mechanical stimuli and produced loss of locomotion and loss of bladder function, syndromes seen clinically after SCI.\r\nTreatment after SCI with recombinant neutrophil inhibitory factor (rNIF) was tested to determine if inhibition of neutrophils, a primary inflammatory cell, in the first 24 hours after injury would improve outcome measures. Treatment with rNIF reduced neutrophil infiltration after injury by greater than 50% and resulted in decreased sensitivity to mechanical stimuli and improved bladder function. Additionally, the amount of white and grey matter lost secondary to SCI was reduced.\r\nSince neutrophils release proteinases, generate reactive oxygen species, phagocytize cells and influence inflammatory cytokine expression, pro- and anti-inflammatory cytokine protein levels were measured at specific time points after SCI, in both the spinal parenchyma and blood serum. Treatment with rNIF had a significant effect on cytokine expression after injury.\r\nThese results demonstrate the effectiveness of inhibiting secondary injury after SCI using rNIF and one mechanism for improved outcomes may be the altered the expression pattern of pro- and anti-inflammatory cytokines which may contribute to dysfunctional outcomes after SCI.\r\nItem Neuropathic pain and the inhibition of learning within the spinal cord(Texas A&M University, 2004-09-30) Ferguson, Adam RichardPrior work from our laboratory has shown that the spinal cord is capable of supporting a simple form of instrumental (response-outcome) learning. In a typical experiment, animals are given a spinal transection at the second thoracic vertebra, and tested 24 h after surgery. If animals are given shock when their leg is in a resting position (controllable shock), they quickly learn to maintain the leg in a flexed position, thereby minimizing shock exposure. Animals exposed to shock that is independent of leg position (uncontrollable shock) fail to learn. This learning deficit can be induced by as little as 6 minutes of shock to either limb or to the tail, and lasts for up to 48 h. The aim of this dissertation was to explore whether the deficit shares behavioral features and pharmacological mechanisms similar to those involved in the induction of neuropathic pain. Work within the pain literature has identified a spinal hyperexcitability that is induced by intense stimulation of pain fibers. This phenomenon, known as central sensitization, is characterized by an increase in tactile reactivity (allodynia) that can be induced by shock or peripheral inflammation. Pharmacological findings have revealed that central sensitization depends on the activation of the N-methyl-D-aspartate (NMDA) and group I metabotropic glutamate receptors (mGluRs). Experiment 1 showed that uncontrollable shock induces a tactile allodynia similar to that observed in central sensitization. Experiment 2 showed that peripheral inflammation caused by a subcutaneous injection of formalin generates a dose-dependent deficit. Experiment 3 indicated that the formalin-induced deficit was observed 24 h after delivery of the stimulus. Experiments 4-8 revealed that the NMDA and group I mGluRs are involved in the deficit. The NMDA receptor was found to be necessary (Experiment 4), but only sufficient to induce a deficit at neurotoxic doses (Experiment 5). Both of the group I mGluRs (subtypes, mGluR1 and mGluR5) were found to be necessary (Experiments 6 & 7). A general group I mGluR agonist summated with a subthreshold intensity of shock to produce a robust deficit (Experiment 8), suggesting shock and mGluR activation produce a deficit through a common mechanism.