Long J B, Rigamonti D D, Oleshansky M A, Wingfield C P, Martinez-Arizala A
Department of Medical Neurosciences, Walter Reed Army Institute of Research, Washington, District of Columbia.
J Pharmacol Exp Ther. 1994 Apr;269(1):358-66.
Dynorphin A reduced lumbosacral blood flow, elevated cerebrospinal fluid lactic acid concentrations and caused flaccid hindlimb paralysis and striking neuropathological changes after its injection into the spinal subarachnoid space in rats. Coadministration of the vasodilator hydralazine substantially eliminated the paralytic, anaerobic metabolic and neuropathological responses to dynorphin A. In contrast, in concentrations up to 1 mM, dynorphin A did not alter the viability of cultured rat spinal cord neurons. Thus, it appears that this peptide lacks direct neurotoxic effects and that neuronal injuries in vivo result primarily from ischemia associated with dynorphin A-induced blood flow reductions. NMDA receptor antagonists significantly improved recovery from dynorphin A-induced hindlimb paralysis, and substantially eliminated neuropathological changes without attenuating the acute blood flow reductions or lactic acid elevations. Additionally, glutamate and aspartate concentrations were increased significantly in spinal cord cerebrospinal fluid samples removed during the time that peptide-induced spinal cord blood flow reductions were observed. In contrast, neither amino acid concentration was elevated in media removed after 1-hr exposure of spinal cord neuronal cell cultures to 100 microM concentrations of dynorphin A. These results indicate that the paralysis and spinal cord injuries produced in rats after spinal subarachnoid injection of dynorphin A result predominantly from spinal cord ischemia, and further identify excitatory amino acids and N-methyl-D-aspartate receptor mechanisms as important mediators in this injury model.
强啡肽A注入大鼠脊髓蛛网膜下腔后，可降低腰骶部血流，升高脑脊液乳酸浓度，并导致后肢弛缓性麻痹和显著的神经病理改变。同时给予血管扩张剂肼苯哒嗪可基本消除对强啡肽A的麻痹、无氧代谢和神经病理反应。相比之下，浓度高达1 mM时，强啡肽A不会改变培养的大鼠脊髓神经元的活力。因此，似乎这种肽缺乏直接神经毒性作用，体内神经元损伤主要源于与强啡肽A诱导的血流减少相关的缺血。NMDA受体拮抗剂可显著改善强啡肽A诱导的后肢麻痹的恢复，并基本消除神经病理改变，而不会减弱急性血流减少或乳酸升高。此外，在观察到肽诱导脊髓血流减少的时间段内采集的脊髓脑脊液样本中，谷氨酸和天冬氨酸浓度显著升高。相比之下，脊髓神经元细胞培养物在100 microM浓度的强啡肽A中暴露1小时后，培养基中两种氨基酸浓度均未升高。这些结果表明，脊髓蛛网膜下腔注射强啡肽A后大鼠产生的麻痹和脊髓损伤主要源于脊髓缺血，并进一步确定兴奋性氨基酸和N-甲基-D-天冬氨酸受体机制是该损伤模型中的重要介质。
