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

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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