Ririe Douglas G, Prout Heather D, Barclay David, Tong Chuanyo, Lin Marina, Eisenach James C
Department of Anesthesiology and Center for the Study of Pharmacological Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1009, USA. dririe@wfubmc
Anesthesiology. 2006 Mar;104(3):426-31. doi: 10.1097/00000542-200603000-00008.
Systemic administration of a cyclooxygenase 1 (COX-1) inhibitor reduces hypersensitivity to mechanical stimuli after incisional paw surgery in 4-week-old, but not 2-week-old, animals. The purpose of the current study was to test whether this developmental difference was reflected by differences in COX-1 expression in the spinal cord after surgery.
Rats 2 and 4 weeks of age, paralleling infant and child human neurologic developmental stages, were used. A paw incision was made under general anesthesia and the withdrawal thresholds were measured before and after systemic and intrathecal administration of a COX-1 selective inhibitor (SC560). Immunohistochemistry was used to assess COX-1 protein in the spinal cord, and real-time polymerase chain reaction was used to quantify gene expression of COX-1 mRNA.
Systemic and intrathecal administration of SC560 produced an increase in withdrawal threshold in the 4-week-old, but not in the 2-week-old, animals. Intrathecal SC560 increased withdrawal thresholds in the 4-week-old animals at a dose 100-fold less than with systemic administration. Cyclooxygenase 1 protein in the spinal cord was increased ipsilateral to surgery in the 4-week-old, but not in the 2-week-old, animals. Cyclooxygenase 1 mRNA was increased in the 4-week-old animals in the spinal cord ipsilateral to surgery relative to the contralateral side of the spinal cord, but not in the 2-week-old animals.
These results suggest that developmental differences in COX-1 expression in the spinal cord likely explain the lack of efficacy of COX-1 inhibitors in the 2-week-old rats. Whether this reflects a deficit in factors that stimulate COX-1 expression or a difference in response to these factors is not addressed, but should similar deficits occur in humans, COX-1 inhibitors may exhibit reduced efficacy in infants.
给予环氧化酶1（COX-1）抑制剂进行全身给药可降低4周龄动物切开爪手术后对机械刺激的超敏反应，但对2周龄动物无效。本研究的目的是测试这种发育差异是否通过手术后脊髓中COX-1表达的差异来体现。
使用2周龄和4周龄的大鼠，分别对应人类婴儿和儿童的神经发育阶段。在全身麻醉下进行爪切口，并在全身和鞘内给予COX-1选择性抑制剂（SC560）之前和之后测量撤针阈值。使用免疫组织化学评估脊髓中的COX-1蛋白，并使用实时聚合酶链反应定量COX-1 mRNA的基因表达。
全身和鞘内给予SC560可使4周龄动物的撤针阈值升高，但对2周龄动物无效。鞘内给予SC560使4周龄动物撤针阈值升高的剂量比全身给药低100倍。4周龄动物脊髓中与手术同侧的COX-1蛋白增加，但2周龄动物未增加。相对于脊髓对侧，4周龄动物脊髓中与手术同侧的COX-1 mRNA增加，但2周龄动物未增加。
这些结果表明，脊髓中COX-1表达的发育差异可能解释了COX-1抑制剂在2周龄大鼠中无效的原因。这是否反映了刺激COX-1表达的因素存在缺陷或对这些因素的反应差异尚未明确，但如果人类也出现类似缺陷，COX-1抑制剂在婴儿中的疗效可能会降低。
