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

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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.