Mechanisms of Neuropathic Pain

摘要 神经病理性疼痛的一个重要机制是脊髓背角神经元的可塑性变化，在 它们改变了对外围输入的敏感度。这些变化包括增加或减少的疗效 传入突触输入，通常被称为脊髓LTP和LTD(sLTP和SLTD)，因为这些生理性的 这种现象类似于被广泛研究的长时程增强(LTP)和长时程增强(LTD) 在海马体中。我们假设伤害性外周输入在脊髓丘脑束诱导sLTP。 GABA能抑制中间神经元(Gaban)内神经元(STTn)较多，SLTD较少。这种细胞类型的特定突触 可塑性是由两种不同的游离引起的细胞类型特异的细胞内信号机制介导的 自由基，反过来，是由于这些不同类型的细胞铁含量的差异。三个特定目标测试 这个假说。特定目标1检验伤害性信息输入导致NMDA受体介导的假设 细胞内钙内流导致脊髓中STTn的sLTP和Gaban的SLTD。单细胞 贴片记录将由识别的STTn(标记有逆行运输的染料)和Gaban进行 (使用一只转基因小鼠，其Gaban被绿色荧光蛋白标记)在脊髓切片中。 具体目标2是验证假设，即相同的脊髓伤害性输入在STTn中诱导sLTP 但在Gaban中SLTD是因为参与了两种不同的细胞内信号自由基超氧化物和 羟基自由基。具体目标3是检验加班含有高水平铁的假设，在 通过超氧化物驱动的Fenton化学反应导致羟基自由基的过量产生，以及 这种过度生产随后在加班产生了SLTD。细胞型和自由基型特异性假说 突触的可塑性可能解释了为什么神经损伤经常导致慢性神经病理性疼痛。如果被证明是真的， 这一建议可能会导致几种治疗慢性神经性疼痛的方法。

ABSTRACT An important mechanism underlying neuropathic pain is plastic changes in spinal cord dorsal horn neurons, in that they change sensitivity to peripheral inputs. Such changes include increases or decreases in efficacy of afferent synaptic inputs, often called spinal LTP and LTD (sLTP and sLTD) because these physiological phenomena are similar to the long term potentiation (LTP) and long term depression (LTD) extensively studied in the hippocampus. We hypothesize that nociceptive peripheral input induces sLTP in spinothalamic tract neurons (STTn) but sLTD in GABAergic inhibitory interneurons (GABAn). This cell-type specific synaptic plasticity is mediated by cell-type specific intracellular signaling mechanisms caused by two different free radicals that, in turn, are due to differences in iron content of these different cell types. Three specific aims test this hypothesis. Specific aim 1 tests the hypothesis that nociceptive input causes NMDA receptor-mediated intracellular calcium influx which leads to sLTP in STTn but sLTD in GABAn in the spinal cord. Single cell patch recordings will be made from identified STTn (labeled with a retrogradely transported dye) and GABAn (using a transgenic mouse whose GABAn are tagged with green fluorescent protein) in spinal cord slices. Specific aim 2 is to test the hypothesis that the same nociceptive input to the spinal cord induces sLTP in STTn but sLTD in GABAn because two different intracellular signaling free radicals are involved, superoxide and hydroxyl radical, respectively. Specific aim 3 is to test the hypothesis that GABAn contain high levels of iron, in turn causing over-production of hydroxyl radicals via superoxide-driven Fenton chemical reactions, and that this over-production then produces sLTD in GABAn. This hypothesis of cell-type and free radical-type specific synaptic plasticity may explain why nerve injuries often lead to chronic neuropathic pain. If proven to be true, this proposal may lead to several avenues for treating chronic neuropathic pain.