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

我们发现了一种新的调节脑啡肽活性的内源性抑制物，并基于其对脑啡肽降解酶的抑制活性从脊髓中纯化了脑啡肽。结构分析表明，该因子为L-V-V-Y-P-W-T，命名为多杀菌灵。对猴脑二肽基肽酶III(EC3.4.14.4：DPPIII)、氨基肽酶(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，对DPPIII(Ki：5.1×10~(-7))的抑制作用最强。Spinogin还通过抑制中性粒细胞(PMN)上FMLP与其受体的结合来抑制PMN的功能。最近，我们报道了这种针对DPP111的抑制剂可以显著抑制缓激肽诱导的反应。与吗啡相比，它的镇痛作用方式不同。其镇痛作用可能是通过抑制脑啡肽降解酶DPPIII的活性而实现的。确定Spin或更具活性的相关化合物是否能抑制已知对吗啡不敏感的神经病理性疼痛将是一件有趣的事情。旋吗啡在疼痛中起着重要作用，对其类似物的进一步研究可能会导致发现一种新型的药物，该药物将用于各种临床应用

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