The mechanism of axonal injury and regeneration after intrathecal administration of local anesthetics

已知高浓度的局麻药具有神经毒性。然而，它们的神经毒性机制尚不清楚。我们已经报道，在脊髓鞘内注射高浓度丁卡因会增加谷氨酸浓度，并以剂量依赖的方式引起神经元损伤。我们研究了其他局麻药是否也是如此，以及AMPA受体拮抗剂(YM872)是否可以减少高浓度局麻药引起的神经元损伤。将利多卡因(10%)、丁卡因(2%)、布比卡因(2%)和罗比卡因(2%)注入马尾神经水平，并在腰椎脊髓水平植入鞘内微透析探头。用微透析法监测腰髓水平的谷氨酸浓度。给药一周后进行神经学和组织学评估。在利多卡因、丁卡因、布比卡因和罗比卡因后，谷氨酸的峰值浓度分别比基准值高10倍、6倍、5倍和2.5倍。神经细胞损伤程度依次为利多卡因+GT>丁卡因+GT>布比卡因+GT>罗比卡因，鞘内注射YM872后1周感觉和运动功能有下降趋势。YM872可减弱丁卡因引起的运动神经元染色变性。提示鞘内注射局麻药后，脑脊液中谷氨酸浓度升高是常见的P现象，谷氨酸至少在局麻药神经毒性机制中起一定作用。

High concentrations of local anesthetics have been known to be neurotoxic. However, the mechanism for their neurotoxicity Is obscure. We have reported that high concentrations of tetracaine administered intrathecally in the spinal cord increase glutamate concentrations and cause neuronal injury in a dose dependent manner. We investigated whether this is true in other local anesthetics and whether an AMPA receptor antagonist (YM872) can reduce neuronal injury caused by high concentrations of local anesthetics.Lidocaine (10%) , tetracaine (2%), bupivacaine (2%), and ropivacaine (2%) were 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 spinal cord level were monitored by microdialysis. Neurologic and histologic assessment was done one week after the administration. The peak concentrations of glutamate after lidocaine, tetracaine, bupivacaine, and ropivacaine were 10-fold, 6-fold, 5-fold, and 2.5-fold greater than baseline values, respectively. The degree of neuronal injury was in order of lidocaine > tetracaine > bupivacaine > ropivacaine.Intrathecal administration of YM872 tended to reduce sensory and motor function at one week after administration of tetracaine. A chromatolytic change of the motor neuron caused by tetracaine was attenuated by YM872.These results suggest that increased concentrations of glutamate in the cerebrospinal fluid is the common p phenomenon after intrathecal administration of local anesthetics and that glutamate plays, at least in part, an role in the mechanism of neurotoxicity by local anesthetics