Approach of a new pain-regulated substance spinophrin from bovine spinal cord and its application

我们发现了一种新的内源性抑制剂，调节脑啡肽的活性，并从脊髓中纯化，基于其对脑啡肽降解酶的抑制活性。结构分析表明该因子为L-V-V-Y-P-W-T，命名为spinophrin。对猴脑二肽基肽酶III（EC3.4.14.4：DPPIII）、氨肽酶（EC3.4.1：AP）、中性内肽酶（EC3.4.24.11：NEP）、血管紧张素转换酶（EC3.4.15.1：ACE）均有抑制作用，尤其对DPPIII有抑制作用（Ki：5.1x10-7）。Spinorphin还通过抑制FMLP与其在PMN上的受体结合来抑制多形核中性粒细胞（PMN）功能。最近，我们报道了这种针对DPP 111的抑制剂显著抑制缓激肽诱导的反应。与吗啡相比，它以不同的方式显示镇痛作用。它的镇痛作用可能是由对脑啡肽降解酶DPPIII的抑制活性引起的。这将是有趣的，以确定是否spinorphin或更积极的相关化合物抑制神经性疼痛，已知是不敏感的吗啡。Spinorphin在疼痛中起着重要作用，对其类似物的进一步研究将有助于发现一类新型的药物，并将在临床上得到广泛的应用

We found a novel endogenous inhibitor that modulated enkephalin activity and purified it from spinal cord based on its inhibitory activity toward enkephalin-degrading enzymes. Structural analysis revealed the factor to be L-V-V-Y-P-W-T and it was named spinophrin. It inhibits dipeptidyl peptidaseIII(EC3.4.14.4:DPPIII) as well as aminopeptidase(EC3.4.1:AP), neutral endopeptidase(EC3.4.24.11: NEP), angiotensin-converting enzyme (EC3.4.15.1:ACE) from monkey brain, especially to DPPIII(Ki: 5.1x10-7). Spinorphin also inhibited polymorphonuclear neutrophil(PMN) function by suppressing FMLP binding to its receptor on PMNs. Recently we reported that this inhibitor against DPP111 significantly inhibited bradykinin-induced responses. It showed analgesia in a different manner compared with morphine. Its analgesia may be caused by an inhibitory activity toward enkephalin-degrading enzyme, DPPIII. It would be interesting to determine whether spinorphin or more active related compounds inhibit neuropathic pain, known to be insensitive to morphine. Spinorphin plays important roles in pain and further search of its analogues may lead to finding of a novel type of drugs which will be useful for various clinical application