Combining ketamine with astrocytic inhibitor as a potential analgesic strategy for neuropathic pain ketamine, astrocytic inhibitor and pain.
Combining ketamine with astrocytic inhibitor as a potential analgesic strategy for neuropathic pain ketamine, astrocytic inhibitor and pain.
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DOI：
10.1186/1744-8069-6-50
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发表时间：
2010-09-06
期刊：
影响因子：
3.3
通讯作者：
Li YQ
中科院分区：
文献类型：
--
作者：
Mei XP;Wang W;Wang W;Zhu C;Chen L;Zhang T;Xu LX;Wu SX;Li YQ
神经病理性疼痛是一个棘手的临床问题。鞘内注射氯胺酮是一种非竞争性N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，可抑制脊髓神经元的活动，用于临床治疗神经病理性疼痛。然而，新兴的研究已经披露，脊髓星形胶质细胞在神经病理性疼痛的启动和维持中发挥了关键作用。然而，目前的临床治疗仍然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毒素L-α-氨基己二酸酯（LAA）对脊神经结扎（SNL）诱导的神经病理性疼痛的影响。鞘内注射氯胺酮（10、100、1000 μg/kg）或LAA（10、50、100 nmol）均能剂量依赖性地减轻SNL诱发的机械性痛觉超敏。鞘内注射氯胺酮（100、1000 μg/kg）或LAA（50、100 nmol）可下调磷酸化NR 1（pNR 1）和胶质细胞酸性蛋白（GFAP）的表达。氯胺酮（100 μg/kg）与LAA（50 nmol）联合给药对神经性疼痛的作用优于单独鞘内注射氯胺酮或LAA。联合用药能明显缓解机械性痛觉超敏，且起效快、稳定。此外，下调pNR 1和GFAP表达也加强了药物联合给药。这些结果表明，将NMDAR拮抗剂氯胺酮与星形胶质细胞抑制剂或细胞毒素（其一旦合成就适合于临床使用）组合可能是用于神经性疼痛的临床管理的潜在策略。
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.
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