Browsing by Subject "glutamate"
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Item 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.Item Roles of interleukin-1 beta in glutamate-induced spinal cord injury(2006-11-15) Song Liu; David McAdoo; Raymond Grill; Ping Wu; Allan Brasier; Alex KuroskyGlutamate release contributes to the impairments caused by spinal cord injury (SCI). This study addresses the mechanisms of glutamate toxicity involving activation of interleukin-1â (IL-1â). To assess the effects of glutamate on IL-1â and its natural blocking agent interleukin-1 receptor antagonist (IL-1ra), ELISA assays were used to measure the responses of endogenous IL-1â and IL-1ra to glutamate administered to the spinal cord. Levels of activated IL-1â and IL-1ra changed in a reciprocal fashion starting 1 hour after glutamate exposure. Exposure to glutamate initially increases IL-1â expression while it decreases IL-1ra. IL-1â then decreases and IL-1ra increases. IL-1â and IL-1ra change reciprocally in the same fashion in a contused spinal cord. To check whether this mutual effect is due to actions of IL-1â and IL-1ra on each other, IL-1â was applied on the spinal cord and then IL-1ra was measured. IL-1ra was applied onto the cord and IL-1â was measured as well. The results show that administration of IL-1â stimulates the production of IL-1ra and administration of IL-1ra suppresses the activation of IL-1â. To identify subtypes of glutamate receptors involved in this phenomenon, NMDA and AMPA receptor agonists were separately applied to the spinal cord and IL-1â and IL-1ra expression in the cord were measured with ELISA assays. Activation of both the AMPA and the NMDA receptors also induced reciprocal changes between the IL-1â and IL-1ra levels. To determine the effects of activating AMPA and NMDA receptors on IL-1â and IL-1ra, MK801 and NBQX were applied individually on the spinal cord with glutamate. The results show that both AMPA and NMDA receptors are involved in glutamate-induced reciprocity between IL-1â and IL-1ra. To determine if this reciprocity between the expression of IL-1â and IL-1ra affected post-SCI locomotor function, recombinant IL-1â and IL-1ra were administered to glutamate-exposed spinal cords. The Basso-Beattie-Bresnahan (BBB) test of functional recovery demonstrated that IL-1â impaired rat locomotive ability and that IL-1ra improved the recovery of the rats from glutamate-induced locomotor impairment. To explore the mechanism of this IL-1â involvement in excitotoxicity, MAPK activities responding to glutamate were measured and the results showed that both ERK1/2 and p38 are involved in IL-1â induced SCI. Cell death assays showed that apoptosis is caused by glutamate-induced SCI. Overall, we established the following pathway from spinal cord injury to functional impairment: SCI → glutamate release → IL-1â and IL-1ra changes → ERK1/2 and p38 activation → cell death → functional impairment. This is the first pathway traced from glutamate release to functional impairments.