Hama A T, Unnerstall J R, Siegan J B, Sagen J
Department of Anatomy and Cell Biology, University of Illinois at Chicago 60612, USA.
Brain Res. 1995 Jul 31;687(1-2):103-13. doi: 10.1016/0006-8993(95)00476-7.
Excessive activation of N-methyl-D-aspartate (NMDA) receptors in the spinal cord consequent to peripheral injury has been implicated in the initiation of neuropathologic events leading to a state of chronic hyperexcitability and persistence of exaggerated sensory processing. In other CNS disease or injury states, NMDA-mediated neurotoxic damage is associated with a loss of NMDA receptors, and outcome may be improved by agents reducing NMDA activation. Previous findings in our laboratory have demonstrated that the transplantation of adrenal medullary tissue into the spinal subarachnoid space can alleviate sensory abnormalities and reduce the induction of a putative nitric oxide synthase consequent to peripheral nerve injury. In order to determine changes in NMDA receptor expression in the spinal cord following peripheral nerve injury and adrenal medullary grafting, NMDA receptor binding using a high-affinity competitive NMDA receptor antagonist, CGP-39653, and NMDAR1 subunit distribution using immunocytochemistry were investigated. Two weeks following peripheral nerve injury by loose ligation of the right sciatic nerve, either adrenal medullary or striated muscle (control) tissue pieces were implanted in the spinal subarachnoid space. Binding studies revealed a marked reduction in [3H]CGP-39653 binding at L4-L5 levels ipsilateral to peripheral nerve injury in control transplanted animals. In contrast, NMDA binding was normalized in adrenal medullary grafted animals. In addition, NMDAR1 immunoreactivity was reduced in both the dorsal horn neuropil and motor neurons of the ventral horn in animals with peripheral nerve injury, while levels in adrenal medullary grafted animals appeared similar to intact controls. These results suggest that adrenal medullary transplants reduce abnormal sensory processing resulting from peripheral injury by intervening in the spinal NMDA-excitotoxicity cascade.
外周损伤后脊髓中N-甲基-D-天冬氨酸（NMDA）受体的过度激活与导致慢性过度兴奋状态和夸张感觉处理持续存在的神经病理事件的起始有关。在其他中枢神经系统疾病或损伤状态下，NMDA介导的神经毒性损伤与NMDA受体的丧失有关，并且通过减少NMDA激活的药物可能改善结果。我们实验室先前的研究结果表明，将肾上腺髓质组织移植到脊髓蛛网膜下腔可以减轻感觉异常，并减少外周神经损伤后假定的一氧化氮合酶的诱导。为了确定外周神经损伤和肾上腺髓质移植后脊髓中NMDA受体表达的变化，使用高亲和力竞争性NMDA受体拮抗剂CGP-39653研究了NMDA受体结合，并使用免疫细胞化学研究了NMDAR1亚基分布。在通过右侧坐骨神经松散结扎造成外周神经损伤两周后，将肾上腺髓质或横纹肌（对照）组织块植入脊髓蛛网膜下腔。结合研究显示，在对照移植动物中，外周神经损伤同侧L4-L5水平的[3H]CGP-39653结合明显减少。相比之下，在肾上腺髓质移植的动物中NMDA结合正常化。此外，在外周神经损伤动物的背角神经毡和腹角运动神经元中，NMDAR1免疫反应性均降低，而肾上腺髓质移植动物中的水平似乎与完整对照相似。这些结果表明，肾上腺髓质移植通过干预脊髓NMDA兴奋性毒性级联反应来减少外周损伤引起的异常感觉处理。
