Kest B, Orlowski M, Molineaux C J, Bodnar R J
Department of Psychology, Queens College, CUNY, Flushing 11367.
Int J Neurosci. 1991 Jan-Feb;56(1-4):141-9. doi: 10.3109/00207459108985410.
Endopeptidase 24.15, a metalloendopeptidase active in brain, rapidly converts prodynorphin-derived peptides into leu-enkephalin. Inhibitors of this enzyme slow the degradation of these peptides in vivo and in vitro. The present study evaluated two inhibitors of endopeptidase 24.15, N-[1-(RS)-carboxy-3-phenyl-propyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), and N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-D-Ala-Phe-p-aminobenzoate (cFP-A(D)AF-pAB), for antinociception on the tail-flick and jump tests in rats following intracerebroventricular administration relative to an inhibitor of endopeptidase 24.11, N-(1-(RS)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (cFP-F-pAB). cFP-AAF-pAB, cFP-A(D)AF-pAB and cFP-F-pAB produced equipotent dose-dependent (25-250 nmol) and time-dependent (5-7 h) antinociception with larger effects on the jump (49-51% increase) relative to the tail-flick (28-41% increase) test. Naloxone (1 mg/kg, SC) significantly reduced antinociception elicited by all inhibitors on the jump test. Motor performance failed to be affected by inhibitor administration. The gradual appearance of antinociception and its naloxone sensitivity suggest that these effects are mediated through inhibition of opioid peptide degradation.
内肽酶24.15是一种在大脑中具有活性的金属内肽酶，它能迅速将强啡肽原衍生肽转化为亮氨酸脑啡肽。该酶的抑制剂可在体内和体外减缓这些肽的降解。本研究评估了两种内肽酶24.15抑制剂，即N-[1-(RS)-羧基-3-苯基丙基]-丙氨酸-丙氨酸-苯丙氨酸-对氨基苯甲酸酯（cFP-AAF-pAB）和N-[1-(RS)-羧基-3-苯基丙基]-丙氨酸-D-丙氨酸-苯丙氨酸-对氨基苯甲酸酯（cFP-A(D)AF-pAB），相对于内肽酶24.11抑制剂N-(1-(RS)-羧基-3-苯基丙基]-苯丙氨酸-对氨基苯甲酸酯（cFP-F-pAB），在脑室内给药后对大鼠甩尾和跳跃试验的镇痛作用。cFP-AAF-pAB、cFP-A(D)AF-pAB和cFP-F-pAB产生等效的剂量依赖性（25 - 250 nmol）和时间依赖性（5 - 7小时）镇痛作用，相对于甩尾试验（增加28 - 41%），对跳跃试验的作用更大（增加49 - 51%）。纳洛酮（1 mg/kg，皮下注射）显著降低了所有抑制剂在跳跃试验中引起的镇痛作用。抑制剂给药未影响运动表现。镇痛作用的逐渐出现及其对纳洛酮的敏感性表明，这些作用是通过抑制阿片肽降解介导的。
