The mechanism for neurotoxicity of local anesthetics

已知高浓度的局麻药具有神经毒性。然而，其神经毒性的机制尚不清楚。本实验研究了鞘内注射肾上腺素或不注射肾上腺素的局麻药对脑脊液中谷氨酸浓度和神经元损伤的影响。在兔腰髓水平鞘内植入微透析探头后，鞘内注射丁卡因(0.3mL)。用微透析法监测腰椎脑脊液中谷氨酸浓度。给药一周后进行神经学和组织病理学评估。丁卡因以剂量依赖的方式增加谷氨酸浓度。注射1%、2%和4%丁卡因后，谷氨酸的峰值浓度分别是基线的4倍、6倍和10倍。在丁卡因中加入肾上腺素(0.1 mg/mL)并不能增加谷氨酸的峰值浓度，但维持较高的谷氨酸浓度。给予1%丁卡因的动物神经学上都是正常的。被注射4%丁卡因的动物都不能跳跃。感觉和运动功能障碍动物的组织学特征是背索空泡化和腰髓运动神经元染色变性损伤。结果提示，脑脊液中谷氨酸浓度的升高可能与局麻药的神经毒性机制有关，肾上腺素的加入可减轻丁卡因的神经毒性。

High concentrations of local anesthetics have been known to be neurotoxic. However, the mechanism for its neurotoxicity is obscure. We investigated the effect of local anesthetics with or without epinephrine injected intrathecally in the lumbar spinal cord on the concentrations of glutamate in the cerebrospinal fluid and neuronal injury.Tetracaine (0.3 mL) was administered intrathecally at the cauda equina level to the rabbits implanted with an intrathecal microdialysis probe at the lumbar spinal cord level. Glutamate concentrations in the lumbar cerebrospinal fluid were monitored by microdialysis. Neurologic and histopathologic assessments were done one week after the administration. Tetracaine increased glutamate concentrations in a dose-dependent manner. The peak concentrations of glutamate after administration of 1%, 2%, and 4% tetracaine were 4-fold, 6-fold, and 10-fold higher than baseline values, respectively. Addition of epinephrine (0.1 mg/mL) to tetracaine did not augment the peak concentrations of glutamate but sustained high concentrations of glutamate. Animals given 1% tetracaine were all neurologically normal. No animal given 4% tetracaine was able to hop. Characteristic histologic changes in animals with sensory and motor dysfunction were vacuolation in the dorsal funiculus and chromatolytic damagc of motor neurons in the lumbar spinal cord. The vacuolation of the dorsal funiculus was worsened by the addition of epinephrine to tetracaine.These results suggest that increased concentrations of glutamate in the cerebrospinal fluid may possibly be related to the mechanism for neurotoxicity of local anesthetics and that addition of epinephrine to tetracaine may inerease its neurotoxicity.