Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity.
Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity.
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DOI：
10.1213/ane.0b013e3182501a09
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发表时间：
2012-08
影响因子：
5.7
通讯作者：
Yaksh TL
中科院分区：
文献类型：
--
作者：
Walker SM;Grafe M;Yaksh TL
椎管内可乐定用于所有年龄段儿童的围手术期镇痛。对出生后大鼠的临床前研究可以比较脊髓镇痛药在整个出生后发育过程中的相对毒性和安全性。将出生后 3、7 或 21 天的幼鼠短暂麻醉，以鞘内注射盐水或可乐定。在每个年龄，确定最大耐受剂量、抗伤害性（增加后肢机械缩回阈值）和抗痛觉过敏（后爪角叉菜胶炎症）剂量。评估腰脊髓切片的细胞凋亡和细胞死亡（组织学、活化的 caspase-3 免疫组织化学、Fluoro-Jade C 染色）、组织病理学（苏木精和伊红染色）和神经胶质反应性增加（小胶质细胞和星形细胞标记）。 P3鞘内氯胺酮切片作为阳性对照。在其他组中，在 P35 时测量热潜伏期和机械缩回阈值。鞘内注射可乐定对幼鼠产生年龄和剂量依赖性镇痛作用。可乐定的最大剂量不会改变细胞凋亡的程度或分布，也不会增加新生儿脊髓中的神经胶质反应性。任何年龄的注射后 1 或 7 天均未发现脊柱组织病理学变化。鞘内注射可乐定在 P35 时不会对机械或热刺激的反射敏感性产生持续变化。产后大鼠鞘内注射可乐定，即使剂量远大于镇痛所需剂量，也不会产生脊髓毒性迹象。 P3时的治疗比（最大耐受剂量/抗痛觉过敏剂量）>300，P7时>30，P21时>10。这些数据提供了额外的信息，为生命早期脊髓镇痛剂的临床选择提供信息。
Neuraxial clonidine is utilized for peri-operative analgesia in children of all ages. Preclinical studies in the postnatal rat allow comparison of the relative toxicity and safety of spinal analgesics throughout postnatal development. Rat pups aged 3, 7 or 21 postnatal (P) days were briefly anesthetized for intrathecal injections of saline or clonidine. At each age, the maximum tolerated, anti-nociceptive (increased hindlimb mechanical withdrawal threshold) and anti-hyperalgesic (hindpaw carrageenan inflammation) doses were determined. Lumbar spinal cord sections were assessed for apoptosis and cell death (histology, activated caspase-3 immunohistochemistry, Fluoro-Jade C staining), histopathology (haematoxylin and eosin staining), and increased glial reactivity (microglial and astrocytic markers). P3 intrathecal ketamine sections served as positive controls. In additional groups, thermal latency and mechanical withdrawal threshold were measured at P35. Intrathecal clonidine produces age- and dose-dependent analgesia in rat pups. Maximal doses of clonidine did not alter the degree or distribution of apoptosis or increase glial reactivity in the neonatal spinal cord. No spinal histopathology was seen 1 or 7 days following injection at any age. Intrathecal clonidine did not produce persistent changes in reflex sensitivity to mechanical or thermal stimuli at P35. Intrathecal clonidine in the postnatal rat did not produce signs of spinal cord toxicity, even at doses much greater than required for analgesia. The therapeutic ratio (maximum tolerated dose/anti-hyperalgesic dose) was >300 at P3, >30 at P7, and >10 at P21. These data provide additional information to inform the clinical choice of spinal analgesic agent in early life.