Pharmacological Study of Substance P and Dynorphin on the Spinal Regulation of Nociceptive Information

在小鼠福尔马林实验中，观察了蛋白酶抑制剂对鞘内给药dynorphin （Dyn）诱导的抗孕毒作用。半胱氨酸蛋白酶抑制剂对羟基汞苯甲酸酯（PHMB）和内肽酶24.11抑制剂磷酰胺（phospamidon）都延长了dyn诱导的抗伤感觉。然而，卡托普利，一种血管紧张素转换酶抑制剂，贝司他汀（一种通用的氨肽酶抑制剂）和一种丝氨酸蛋白酶抑制剂苯甲磺酰氟，是无活性的。[Leu^5]脑啡肽（Leu- enk）和Leu- enk - arg ^6，即Dyn由半胱氨酸蛋白酶产生的产物，都没有产生任何抗伤感受作用。然而，Leu-Enk- arg ^6，而不是Leu-Enk，在与磷酰胺共给药时产生显著的抗伤害感受作用。因此，在磷酰胺存在的情况下，Dyn诱导的抗孕毒作用的延长可能是由于抑制了Leu-Enk-Arg^6的降解。此外，在小鼠辣椒素试验中，比较了在贝司他汀存在的情况下，给药PHMB与磷酰胺的抗伤性作用。PHMB和磷酰胺/贝司他汀均能诱导抗伤感受作用。PHMB和磷酰胺/贝司他汀分别被选择性受体拮抗剂no - bni和选择性受体拮抗剂naltrindole抑制。本研究结果表明，半胱氨酸蛋白酶可能是终止dyn诱导的抗痛觉作用的重要酶，PHMB和磷酰胺/贝司他汀的抗痛觉作用可能是由于抑制内源性dyn和脑啡肽的降解。

The effects of protease inhibitors on the antinociception induced by intrathecally (i.t.) administered dynorphin (Dyn) in the mouse formalin test were examined. Both p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, and phosphoramidon, an endopeptidase 24.11 inhibitor, prolonged Dyn-induced antinociception. However, captopril, an angiotensin-converting enzyme inhibitor, bestatin (a general aminopeptidase inhibitor) and a serine protease inhibitor phenylmethanesulfonyl fluoride, were inactive. Neither [Leu^5] enkephalin (Leu-Enk) nor Leu-Enk-Arg^6, the products of Dyn by cysteine proteases, produced any antinociceptive effect. However, Leu-Enk-Arg^6, but not Leu-Enk, produced a significant antinociceptive effect when coadministered with phosphoramidon. Therefore, the prolongation of the antinociception induced by Dyn in the presence of phosphoramidon may be due to the inhibition of Leu-Enk-Arg^6 degradation. Moreover, the antinociceptive effect of i.t. administered PHMB was compared with that of phosphoramidon in the presence of bestatin in the mouse capsaicin test. Both PHMB and phosphoramidon/bestatin induced the antinociceptive effect. The antinociceptive effect induced by PHMB and phosphoramidon/bestatin was inhibited by nor-BNI,a selective kappa receptor antagonist, and naltrindole, a selective delta receptor antagonist, respectively. The present results indicate that cysteine proteases may be important enzymes in terminating Dyn-induced antinociception and the antinociceptive effect of PHMB and phosphoramidon/bestatin may be due to the inhibition of the degradation of endogenous Dyns and enkephalins, respectively.