Coquerel A, Dubuc I, Kitaegi P, Costentin J
Unité de Neuropsychopharmacologie Expérimentale, U.A. 1170 CNRS, Faculté de Médecine & Pharmacie de Rouen, B.P. 97, 76800 Saint Etienne du Rouvray, France.
Neurochem Int. 1988;12(3):361-6. doi: 10.1016/0197-0186(88)90175-1.
Neurotensin induced significant antinociceptive activity as measured in a variety of nociceptive tests 10 and 30 min following intracerebroventricular (i.c.v.) injection in mice. The lowest effective peptide doses were 25 ng in the writhing test, 25-50 ng in the tail-flick test, 50-100 ng in the hot-plate test and 2000 ng in the tail electrical stimulation test. The neurotensin related hexapeptide neuromedin N also displayed antinociceptive properties but only in the writhing and tail-flick tests. Furthermore, as compared to neurotensin, the neuromedin effects required higher doses. ED(50)'s for neurotensin and neuromedin in the writhing test were 70 ng and 1070 ng, respectively. Separate or combined injections of the endopeptidase 24.11 (enkephalinase) inhibitor thiorphan (l0?g) and the aminopeptidase inhibitor bestatin (50?g) did not affect tail-flick latencies. In contrast, i.c.v. injection of thiorphan together with an ineffective dose of neurotensin (25 ng) resulted in a significant antinociceptive effect. Bestatin did not modify tail-flick latencies in neurotensin-treated mice whether in the absence or presence of thiorphan. On the contrary, each of these peptidase inhibitors promoted antinociceptive effects of subthreshold doses of neuromedin (l?g) in the tail-flick test. Maximal antinociception was obtained by combining both inhibitors, thus conferring antinociceptive effects to neuromedin doses that were as low as 10 ng. Naloxone (0.5-2 mg/kg, s.c.) did not significantly reduced the antinociceptive effects of combinations of neurotensin and thiorphan and of neuromedin, thiorphan and bestatin. The data show that both neurotensin and neuromedin elicit analgesia in mice through an opiate independent mechanism. Furthermore, like enkephalin, neuromedin is readily degraded by brain endopeptidase 24.11 and bestatin sensitive aminopeptidase(s), whereas the resistance of neurotensin to aminopeptidase attack confers to this peptide a broader spectrum and longer duration of action than its congener neuromedin.
在小鼠脑室内（i.c.v.）注射后10分钟和30分钟，通过多种伤害感受性测试测量发现，神经降压素诱导出显著的抗伤害感受活性。在扭体试验中最低有效肽剂量为25纳克，在甩尾试验中为25 - 50纳克，在热板试验中为50 - 100纳克，在尾部电刺激试验中为2000纳克。与神经降压素相关的六肽神经介素N也表现出抗伤害感受特性，但仅在扭体和甩尾试验中。此外，与神经降压素相比，神经介素的作用需要更高剂量。在扭体试验中，神经降压素和神经介素的半数有效剂量（ED(50)）分别为70纳克和1070纳克。单独或联合注射内肽酶24.11（脑啡肽酶）抑制剂硫喷妥（10微克）和氨肽酶抑制剂贝司他汀（50微克）不影响甩尾潜伏期。相反，脑室内注射硫喷妥与无效剂量的神经降压素（25纳克）一起导致显著的抗伤害感受作用。无论是否存在硫喷妥，贝司他汀都不会改变神经降压素处理小鼠的甩尾潜伏期。相反，在甩尾试验中，这些肽酶抑制剂中的每一种都能促进阈下剂量神经介素（1微克）的抗伤害感受作用。通过联合使用两种抑制剂可获得最大抗伤害感受效果，从而使低至10纳克的神经介素剂量也具有抗伤害感受作用。纳洛酮（0.5 - 2毫克/千克，皮下注射）不会显著降低神经降压素与硫喷妥以及神经介素、硫喷妥和贝司他汀组合的抗伤害感受作用。数据表明，神经降压素和神经介素均通过非阿片类机制在小鼠中引发镇痛作用。此外，与脑啡肽一样，神经介素很容易被脑内肽酶24.11和贝司他汀敏感的氨肽酶降解，而神经降压素对氨肽酶攻击的抗性使其比同类神经介素具有更广泛的作用谱和更长的作用持续时间。
