Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, China.
Mol Pain. 2010 Sep 6;6:50. doi: 10.1186/1744-8069-6-50.
Neuropathic pain is an intractable clinical problem. Intrathecal ketamine, a noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist, is reported to be useful for treating neuropathic pain in clinic by inhibiting the activity of spinal neurons. Nevertheless, emerging studies have disclosed that spinal astrocytes played a critical role in the initiation and maintenance of neuropathic pain. However, the present clinical therapeutics is still just concerning about neuronal participation. Therefore, the present study is to validate the coadministration effects of a neuronal noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine and astrocytic cytotoxin L-α-aminoadipate (LAA) on spinal nerve ligation (SNL)-induced neuropathic pain.
Intrathecal ketamine (10, 100, 1000 μg/kg) or LAA (10, 50, 100 nmol) alleviated SNL-induced mechanical allodynia in a dose-dependent manner respectively. Phosphorylated NR1 (pNR1) or glial fibrillary acidic protein (GFAP) expression was down-regulated by intrathecal ketamine (100, 1000 μg/kg) or LAA (50, 100 nmol) respectively. The combination of ketamine (100 μg/kg) with LAA (50 nmol) showed superadditive effects on neuropathic pain compared with that of intrathecal administration of either ketamine or LAA alone. Combined administration obviously relieved mechanical allodynia in a quick and stable manner. Moreover, down-regulation of pNR1 and GFAP expression were also enhanced by drugs coadministration.
These results suggest that combining NMDAR antagonist ketamine with an astrocytic inhibitor or cytotoxin, which is suitable for clinical use once synthesized, might be a potential strategy for clinical management of neuropathic pain.
神经病理性疼痛是一种难治性临床问题。鞘内给予氯胺酮，一种非竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，据报道可通过抑制脊髓神经元的活性用于治疗临床中的神经病理性疼痛。然而，新出现的研究表明，脊髓星形胶质细胞在神经病理性疼痛的发生和维持中起着关键作用。然而，目前的临床治疗方法仍只关注神经元的参与。因此，本研究旨在验证神经元非竞争性 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂氯胺酮和星形胶质细胞细胞毒素 L-α-氨基己二酸（LAA）联合给药对脊神经结扎（SNL）诱导的神经病理性疼痛的协同作用。
鞘内给予氯胺酮（10、100、1000μg/kg）或 LAA（10、50、100nmol）均可剂量依赖性地缓解 SNL 诱导的机械性痛觉过敏。鞘内给予氯胺酮（100、1000μg/kg）或 LAA（50、100nmol）可分别下调磷酸化 NR1（pNR1）或胶质纤维酸性蛋白（GFAP）表达。与鞘内单独给予氯胺酮或 LAA 相比，氯胺酮（100μg/kg）与 LAA（50nmol）联合给药对神经病理性疼痛具有超相加作用。联合给药可迅速稳定地缓解机械性痛觉过敏。此外，药物联合给药还增强了 pNR1 和 GFAP 表达的下调。
这些结果表明，将 NMDAR 拮抗剂氯胺酮与合成后适合临床应用的星形胶质细胞抑制剂或细胞毒素联合使用，可能是治疗神经病理性疼痛的一种潜在策略。
