Browsing by Subject "spinal cord"
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Item Role of the opioid system in the behavioral deficit observed after uncontrollable shock(Texas A&M University, 2006-08-16) Washburn, Stephanie NicoleSpinal cord neurons can support a simple form of instrumental learning that can be used to assess behavioral potential (plasticity) within this system. In this paradigm, subjects completely transected at the second thoracic vertebra learn to minimize shock exposure by maintaining a hindlimb in a flexed position. Preexposure to uncontrollable shock (shock independent of leg position) disrupts this learning. Activation of opioid receptors seems to contribute to the expression of the behavioral deficit observed after uncontrollable shock. Intrathecal application of naltrexone, a nonselective opioid receptor antagonist, blocked the expression, but not the induction, of the deficit. Treatment with nor-BNI, a kappa receptor antagonist, prior to testing had a similar effect, whereas mu (CTOP) and delta (naltrindole) receptor antagonists did not block the deficit. These findings suggest that prior exposure to uncontrollable shock induces a kappa opioid mediated event that inhibits learning. The current study examined the role of the kappa receptor in the behavioral deficit. Only GR89696, a selective kappa-2 receptor agonist, inhibited learning. This impairment was dose-dependent and, at the highest dose (30 nmol), inhibited learning for 96 hours. However, GR89696 and uncontrollable shock did not interact in an additive fashion. Instead, an intermediate dose attenuated the induction of the deficit. These findings suggest that activation of kappa receptors, specifically the kappa-2 subtype, inhibit instrumental learning and block the induction of the learning deficit. Both effects may be linked to the inhibition of NMDA-mediated plasticity.Item The opponent consequences of intermittent and continuous stimulation within the rat spinal cord(2009-05-15) Puga, Denise AlejandraA substantial body of work exists to suggest that brain and spinal mechanisms react differently to nociceptive information. The current experiments were design to identify parallels and differences in the way the spinal cord processes nociceptive information, as compared to intact animals. In addition, pharmacological manipulations were employed to identify the opioid receptors activated by continuous shock, and to decipher at what synaptic level (e.g. pre or post synaptically) intermittent shock affects the release of endogenous opioids. A common dependent variable was used in all experiments to assess changes in nociceptive reactivity, the tail-flick test. The results revealed that intermittent and continuous stimulation have an opponent relationship on nociceptive processing in the isolated spinal cord. Continuous stimulation (3, 25-s continuous 1.5 mA tail-shocks) induced an antinociceptive response that was attenuated by prior exposure to brief (80 ms) intermittent shock (Experiment 1). When intermittent shock was given after continuous shock, intermittent shock failed to attenuate continuous shock-induced antinociception (Experiment 2). The impact of intermittent shock on continuous-shock induced antinociception decayed after 24 hours (Experiment 3). Intermittent and continuous shock enhanced the antinociceptive consequences of a moderate dose of systemic morphine (5 mg/kg) (Experiment 4). Continuous shock-induced antinociception was attenuated by equal molar concentrations of CTOP (? opioid antagonist) and Nor-BNI (? opioid antagonist), but not naltrindole (? opioid antagonist) (Experiment 5). Intermittent shock failed to attenuate the antinociception induced by DAMGO (? opioid agonist) or Dynorphin A (? opioid agonist).Item The Role of Tumor Necrosis Factor-Alpha in Maladaptive Spinal Plasticity(2012-02-14) Huie, John RussellPrevious work has shown that the spinal cord is capable of supporting a simple form of instrumental learning. Subjects that receive controllable shock to an extended hind limb will increase the duration of limb flexion over time in order to reduce net shock exposure. Exposure to as little as 6 minutes of uncontrollable stimulation prior to instrumental testing can elicit a long-lasting learning deficit. Prior work has suggested that this deficit may reflect an overexcitation of spinal neurons akin to central sensitization, and that learning is inhibited by the saturation of plasticity. The experiments in this dissertation were designed to test the role of the cytokine tumor necrosis factor alpha (TNFa) in the induction and expression of the deficit. It is believed that the inflammatory properties of TNFa may mediate the excitatory processes that lead to maladaptive spinal functioning. Experiments 1 and 2 tested the necessity of endogenous TNFa in the deficit produced by uncontrollable shock. These experiments showed that the inhibition of endogenous TNFa blocks both the induction and expression of the shock-induced deficit, suggesting a necessary role for TNFa in mediating the inhibition of spinal learning. Conversely, Experiment 3 was designed to test the sufficiency for TNFa in producing a learning deficit. I found that treatment with exogenous TNFa undermined spinal learning in a dose-dependent fashion, whether given immediately, or 24 hours prior to testing. Experiment 4 demonstrated that the long-term TNFa-induced deficit is mediated by TNFa receptor activity, as a TNF inhibitor given prior to testing blocked the expression of this deficit. As TNFa has been shown to be predominantly of glial origin, I next assessed the role that glia play in the TNFa-induced deficit. Experiment 5 showed that inhibiting glial metabolism prior to TNFa treatment blocked the capacity for TNFa to produce a long-term deficit. Experiment 6 assessed the potential for TNFa inhibition to block the deficit induced by lipopolysaccharide (LPS), an agent known to induce TNFa. TNFa has also been shown to drive neural excitation by increasing the trafficking of calciumpermeable AMPA receptors to the active zone of the post-synaptic bouton. Experiment 7 showed that selectively antagonizing these receptors prior to testing blocked the TNFa- induced deficit, suggesting a possible post-synaptic mechanism by which TNFa exerts its effects. Finally, histological evidence was sought to reinforce the previous behavioral findings. Experiment 8 used quantitative RT-PCR to assess the differential expression of TNFa mRNA in uncontrollably shocked subjects as compared to those receiving controllable shock and no shock. To determine concentrations of TNFa protein, an ELISA was run in Experiment 9 comparing uncontrollably shocked subjects to unshocked controls.