Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat
Potentiation of [Met5]enkephalin-induced antinociception by mixture of three peptidase inhibitors in rat
复制标题
三种肽酶抑制剂的混合物增强[Met5]脑啡肽诱导的大鼠镇痛作用
DOI：
10.1007/s00540-014-1819-5
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Suzuki T
中科院分区：
文献类型：
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作者：
Murata T;Yoshikawa M;Watanabe M;Takahashi S;Kawaguchi M;Kobayashi H;Suzuki T
目的体外研究表明，阿片肽在与脑细胞膜孵育过程中的降解几乎完全被三种肽酶抑制剂（PI），即amastatin，captopril和phosphoramidon的混合物所阻止。在目前的体内研究中，我们评估的影响，这些PI鞘内给药的抗伤害性感受由[蛋氨酸5]脑啡肽（ME）或PI本身。MethodsDrugs被管理到胸腰段水平的脊髓在大鼠的鞘内空间。通过尾部浸泡试验测量抗伤害感受的诱导，其中55 °C作为伤害性刺激。采用量效关系研究PI的镇痛作用（ME，1-20 nmol; PI，各1-20 nmol），通过比较两种PI组合之间的差异（amastatin和captopril; captopril和phosphoramidon; amastatin和phosphoramidon）和三种PI（amastatin、captopril和phosphoramidon），结果鞘内注射ME与这三种PI或PI单独给药可显著增强μ-和δ-受体的抗伤害作用，并呈剂量依赖性。阿片受体拮抗剂-可逆方式;此外，任何两种组合的抗伤害感受程度低于所有三种组合，表明任何残留的单肽酶都可以抑制显著量的ME。结论本数据以及早期研究的数据清楚地表明，磷酰胺敏感酶在脊髓水平阿片肽失活中起重要作用。
PurposePrevious in vitro studies have shown that degradation of opioid peptides during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors (PIs), namely, amastatin, captopril, and phosphoramidon. In the present in vivo study, we evaluate the effects of intrathecal administration of these PIs on antinociception by [Met5]enkephalin (ME) or PIs themselves.MethodsDrugs were administered into the thoracolumbar level of the spinal cord in the intrathecal space in rat. Induction of antinociception was measured by the tail immersion assay, with 55 °C as the nociceptive stimulus. Effects of PIs on antinociception were evaluated by dose–response study (ME, 1–20 nmol; PIs, 1–20 nmol each), by comparison of differences among two combinations of PIs (amastatin and captopril; captopril and phosphoramidon; amastatin and phosphoramidon) and three PIs (amastatin, captopril, and phosphoramidon), and by using opioid receptor selective antagonists.ResultsIntrathecal administration of ME with these three PIs or PIs alone significantly and dose dependently increased antinociception in a μ- and δ-opioid receptor antagonist-reversible manner; moreover, the degree of antinociception with a combination of any two of these was less than that with all three, indicating that any residual single peptidase could inactivate significant amounts of ME.ConclusionThe present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in inactivation of opioid peptides at the spinal level.