NON NMDA RECEPTORS AND THE DORSAL HORN

AMPA受体介导疼痛传递，并被认为与 启动某些形式的中枢性痛觉过敏的关键成分 超感痛症。Ca~(2+)是第二信使，经常参与可塑性 中枢性突触和某些AMPA受体可直接通透 Ca2+。然而，这些钙离子通透性受体在突触中的作用 可塑性，甚至它们在脊髓突触传递中的作用 (但见初步研究)，是未知的。如果钙离子通过突触进入 AMPA受体负责调节大鼠脑内突触强度 背角疼痛通路，然后进行药物干预 受体将提供一种全新的方法来控制导致 病理性疼痛状态。乔罗蜘蛛毒素(JSTX)，一种多胺 从蜘蛛NePhila clavata中提纯，选择性地阻断钙离子 可穿透的AMPA受体而不阻断不透钙的AMPA受体， 为这种选择性毒品行动提供了一个很好的例子。此外，由于 与钙离子透过性AMPA受体的独特特性相比 NMDA受体，突触通过AMPA受体引起的钙内流 应该通过同时发生的抑制性突触激活来增强(而不是 而不是像NMDA受体那样被抑制)使钙离子- 通透性AMPA受体--一种新型的共入射探测器。 使用合成的JSTX-3，我们有证据证明钙离子- 通透性AMPA受体在背角突触后表达 神经元。我们现在打算阐明钙离子通透性AMPA的作用 受体在疼痛信息的中枢传递和调制中起作用。 我们计划确定钙离子通透性AMPA受体在 对邻近突触受体的修饰依赖于 钙离子通过AMPA通道本身进入。我们已经这么做了 证明钙离子通过钙离子通透性的AMPA受体进入 导致NMDA受体脱敏(Kyrozis等人，1995)，现在 我们将确定这种情况是否发生在突触传递过程中。我们会 通过钙离子通透性AMPA测量进入后的钙蓄积量 受体，并确定其对膜电位的依赖性。我们会 将这些观察结果与突触门控钙离子的观察结果进行对比 镁离子通过NMDA受体蓄积的一种途径 确定钙离子通透性AMPA受体是否可以发挥协同作用 用于抑制输入的事件检测器。最后，我们将确定哪些 背角痛的I、II板层神经元亚群 突触最显著表达钙离子通透性AMPA受体的途径 这些站点将让我们深入了解这些受体所扮演的主要角色 在疼痛的传递中。

AMPA receptors mediate pain transmission and have been implicated as critical components in initiating some forms of central hyperalgesia and allodynia. Ca2+ is a second messenger often involved in plasticity at central synapses and some of the AMPA receptors are directly permeable to Ca2+. However the role of these Ca2+ permeable receptors in synaptic plasticity, even their role in synaptic transmission in the spinal cord (but see Preliminary studies), is unknown. If Ca2+ entry through synaptic AMPA receptors is responsible for regulating synaptic strength in the dorsal horn pain pathway, then pharmacological intervention with those receptors would provide an entirely new way to control conditions leading to pathological pain states. Joro spider toxin (JSTX), a polyamine purified from the spider Nephila clavata, selectively blocks Ca2+ permeable AMPA receptors without blocking Ca2+ impermeable AMPA receptors, providing a good example of such selective drug action. Furthermore, due to the unique properties of the Ca2+ -permeable AMPA receptors compared to NMDA receptors, synaptically evoked Ca2+ entry through the AMPA receptors should be enhanced by co-incident inhibitory synaptic activation (rather than inhibited as is the case for the NMDA receptors) making the Ca2+- permeable AMPA receptors a novel type of co-incidence detector. Using synthetic JSTX-3, we have evidence establishing that the Ca2+- permeable AMPA receptors are expressed postsynaptically on dorsal horn neurons. We now intend to clarify the role of Ca2+-permeable AMPA receptors in the central transmission and modulation of pain information. We plan to determine the role of Ca2+-permeable AMPA receptors in the modification of neighboring synaptic receptors in a manner dependent on Ca2+ entry through the AMPA channels themselves. We have already demonstrated that Ca2+ entry through the Ca2+-permeable AMPA receptors causes desensitization of the NMDA receptors (Kyrozis et al, 1995) and now we will determine if this happens during synaptic transmission. We will measure the Ca2+ accumulation following entry through Ca2+-permeable AMPA receptors and determine its dependence on membrane potential. We will contrast these observations with those made on synaptically gated Ca2+ accumulation through the NMDA receptors in the presence of Mg2+ as a way of determining if Ca2+-permeable AMPA receptors could function as co- incidence detectors for inhibitory input. Finally, we will identify which subpopulation of neurons in laminae I and II of the dorsal horn pain pathway most prominently express Ca2+-permeable AMPA receptors at synaptic sites which will give us insight into the major role these receptors play in pain transmission.