DORSAL HORN/THALAMIC CIRCUITRY

本计划项目的项目4涉及 周围神经损伤后的中枢神经系统。我们将使用 一种实验性的大鼠单神经病变模型，随后在猴子身上， 这会导致以异常为特征的动物的疼痛行为 受影响肢体的姿势和对无害的夸大反应 刺激(痛觉异常)以及伤害性刺激(痛觉过敏)。 几位研究人员已经证明，坐骨神经部分结扎 大鼠的神经导致大量种群的退化 神经中的有髓轴突和无髓轴突。在一项初步研究中，我们 已显示在结扎后14天有广泛的轴突和 大鼠脊髓背角突触变性 动物表现出疼痛行为的时期。其他研究也有 提示在背角存在抑制回路受损。 这样的动物。我们将使用轴突运输结合 免疫细胞化学、电子显微镜技术检测 外周神经后不同时间的背角环路 伤害作为与疼痛相关的行为首先表现出来，直到它 在两个月的时间里逐渐减弱。我们的工作假设是 疼痛行为可以与背角的变化相关， 尤其是在不同存活时间的GABA能回路中。这个 这项研究的第二个主要方面是对 脊髓丘脑束细胞在受影响的节段到丘脑， 工作假说是大脑中的电路发生了变化 丘脑可以与配对行为的变化相关， 尤其是在猴子身上。我们之前已经表明，存在一个 传递配对信息的系统之间也存在明显差异 作为传递关于无害刺激的信息的系统，在 灵长类丘脑。我们认为接受信息输入的丘脑回路 受影响的脊柱节段的数据将因 周围神经损伤。 在人类中，疼痛通常是周围神经损伤的结果。 这里提出的研究可能会导致设计一种基于 在了解脊髓神经回路变化的基础上 周围神经损伤后脊髓和丘脑。特别是，我们 假设脊髓和丘脑的抑制回路是 神经损伤后的变化，随着我们更好地理解 之后发生的神经系统的重组 周围神经损伤，改进的药物治疗旨在 最终可能会开发出解决这些变化的方法。

Project 4 of this Program Project is concerned with changes in the central nervous system that follow peripheral nerve injury. We will use an experimental mononeuropathy model in rat, and subsequently in monkey, which leads to pain behavior in the animals characterized by abnormal posture of the affected limb and exaggerated responses to innocuous stimuli (allodynia) as well as to noxious stimuli (hyperalgesia). Several investigators have shown that partial ligation of the sciatic nerve of the rat leads to degeneration of substantial populations of myelinated and of nonmyelinated axons in the nerve. In a pilot study we have shown that at 14 days postligature there is extensive axonal and synaptic degeneration in the dorsal horn of the rat spinal cord, during a period in which the animal exhibits pain behavior. Other studies have suggested that there is impaired inhibitory circuitry in the dorsal horn of such animals. We will use axon transport combined with immunocytochemical, electron microscopic techniques to examine the circuitry of the dorsal horn at various times following peripheral nerve injury as the pain-related behavior is first manifested until it gradually wanes over a two-month period. Our working hypothesis is that pain behavior can be correlated with changes in the dorsal horn, particularly in the GABAergic circuitry at various survival times. The second major aspect of the study is an examination of the projections of spinothalamic tract ells in the affected segments to the thalamus, the working hypothesis being that there are changes in circuitry in the thalamus that can be correlated with changes in pair behavior, particularly in the monkey. We have previously shown that there is a distinct difference between systems that convey pair information, as well as systems that convey information about innocuous stimuli, in the primate thalamus. We suggest that the thalamic circuitry receiving input from affected spinal segments will be modified as a consequence of the peripheral nerve injury. In humans, pain is often a consequence of peripheral nerve injury and out studies proposed here may lead to a design of rational therapies based upon an understanding of alterations in neural circuitry of the spinal cord and thalamus after peripheral nerve injury. In particular, we hypothesize that the inhibitory circuitry of the cord and thalamus is subject to changes following nerve injury and as we better understand the reorganization of the nervous system that takes place following peripheral nerve injury, improved pharmacological therapies designed to address these changes may ultimately be developed.