A New Pain relief substance in spinal cord ; Parmacological Function and Metabolism of Spinorphin

一种新的脊髓镇痛物质；

• 批准号: 04671424
• 负责人: HAZATO Tadahiko
• 金额: $ 1.28万
• 依托单位: The TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671424/
• 关键词: Spinorphin; Spinal Cord; Pain Relief Substance; Opioid; Endogenous Substance; Inhibitor; Enkephalin-Degrading Enzymes

In this study, We isolated a potent inhibitor for enkephalin-degrading enzymes from the bovine spinal cord, and determined its amino-acid sequence, pharmacological function and metabolism. This new substance is composed of heptapeptide (Leu-Val-Val-Tyr-Pro-Trp-Thr), and has been named by us "Sinorphin". The inhibitory activity (IC_<50>) of this new substance toward enkephalin-degrading enzymes, purified frome monkey brain, was found to be 3.3ug/ml against aminopeptidase, 1.4ug/ml against dipeptidyl aminopeptidase, 2.4ug/ml against angiotensin-converting enzyme, and 10ug/ml against enkephalinase. This substance did not show inhibitory activity toward enkephalins purified kidney and blood. Spinorphin produces a dose-related inhibition of electrically evoked concentrations of both MVD(mouse vas deferens) and GPI(guinea-pig ileum). The intracisternally injected Spinorphin also produced a nalgesic effects in a dose-dependent manner, in dose of 100-200 nmol/mouse.The analgesic effect reached the maximum within 5 minand disapeard after 15-60min. These effects could be completely antagonised by naloxone. Most Spinorphin was degraded when incubated in the human spinal cord for 24hr. However, approximately 86% of the Spinorphin was intact on HPLC when incubated with probestin, which is an inhibitor of Aminopeptidase M.Spinorphin has a high inhibitory activity against enkephalin-degrading enzymes when compared to the various hydrolysis products. In conclusion, the most important structure for opioid activity is Spinorphin. It is suggested that Spinorphin acts as a neuromodulator of enkephalin metabolism in the spinal cord.

在本研究中，我们从牛脊髓中分离出一种脑啡肽降解酶的有效抑制剂，并测定了其氨基酸序列、药理作用和代谢。这种新物质是由七肽(Leu-Val-Val-Tyr-Pro-Trp-Thr)组成的，我们将其命名为辛诺芬。该新物质对从猴脑中提纯的脑啡肽降解酶的抑制活性(IC_(50))分别为3.3ug/ml、1.4ug/ml、2.4ug/ml和10ug/ml。该物质对脑啡肽纯化的肾脏和血液均无抑制活性。多诺芬对电诱发的MVD(小鼠输精管)和GPI(豚鼠回肠)浓度产生剂量相关的抑制作用。脑池内注射Spinnoin也有剂量依赖性的镇痛作用，剂量为100-200nmol/只，镇痛作用在5分钟内达到最大，15-60分钟后消失。纳洛酮可以完全拮抗这些作用。当在人的脊髓中孵育24小时时，大多数多旋吗啡被降解。然而，当与氨肽酶的抑制剂普罗司汀孵育时，旋吗啡大约有86%是完整的。与各种水解物相比，旋吗啡对脑啡肽降解酶有很高的抑制活性。总而言之，阿片类药物活性最重要的结构是旋诺芬。提示Spinogin是脊髓脑啡肽代谢的神经调节剂。

项目成果

Hazato, T.: "Enkephalin and endogenous enkephalinase inhibitor." J.Biochmestry. 66(1). 57-60 (1994)

Hazato, T.：“脑啡肽和内源性脑啡肽酶抑制剂。”

Yamamoto Yukiyo: "AngiotensinII is a new chemo attractant for piymorphonuclear leukcytes" Bio chem Biochys Res. 193. 1038-1043 (1993)

Yamamoto Yukiyo：“血管紧张素 II 是一种针对软核白细胞的新型化学引诱剂”Bio chem Biochys Res。

Nishimura Kinya: "Isolation and Identfication of an on 〓oglnous inhibitor of enkephalin-degrading engymes from bovine spinol corcl" Biochem Biochys Res. 194. 713-719 (1993)

Nishimura Kinya：“从牛脊髓皮质中分离和鉴定脑啡肽降解酶的直接抑制剂”Biochem Biochys Res 194. 713-719 (1993)

Nishimura Kinya: "Study of a new endogenous inhibitor of enkephalin-degrading enzymes:pharmacological function and metabolism of spinorphin" Jap.J Anesthesiology. 42. 1663-1670 (1993)

Nishimura Kinya：“一种新型内源性脑啡肽降解酶抑制剂的研究：螺旋啡的药理功能和代谢”Jap.J Anesthesiology。

Nishimura, K.: "Isolation and identification of an endogenous inhibitor of enkephalin-degrading enzymes from bovine spinal cord." Biochem.Biophys.Res.Commun.194(2). 713-719 (1993)

Nishimura, K.：“从牛脊髓中分离和鉴定脑啡肽降解酶的内源性抑制剂。”