Giorgi O, Pibiri M G, Ongini E, Trampus M, Biggio G
Department of Experimental Biology, University of Cagliari, Italy.
Eur J Pharmacol. 1991 Apr 17;196(2):137-42. doi: 10.1016/0014-2999(91)90419-q.
SCH 32615 is a novel inhibitor of the enzyme, neutral endopeptidase (NEP, E.C. 3.4.24.11), the so called 'enkephalinase', which plays a functional role in the degradation of [Met5]- and [Leu5]enkephalin. The present study was designed to assess whether SCH 32615 is able to modify the activity of dopaminergic neurons as reflected by changes in the content of the major dopamine metabolite, dihydroxyphenylacetic acid (DOPAC), in three different areas of the rat brain: the nucleus accumbens, the striatum, and the prefrontal cortex. When administered at analgesically active doses (1-100 mg/kg s.c., 60 min before killing), SCH 32615 induced a dose-dependent increase in dopamine metabolism in the nucleus accumbens but was ineffective in the striatum and in the prefrontal cortex. This effect appears to be mediated via opioid receptors, since it was completely prevented by naloxone (5 mg/kg s.c.). The increase in DOPAC content in the prefrontal cortex elicited by foot-shock was unaffected by pretreatment with SCH 32615. In the nucleus accumbens, dopamine metabolism was increased to the same extent by foot-shock and SCH 32615 administered separately, but these effects were not additive, suggesting that SCH 32615 and foot-shock act via a common mechanism. Taken together, these results support the hypothesis that inhibition of the in vivo degradation of enkephalins induced by the systemic administration of SCH 32615 increases the enkephalinergic tone in the central nervous system and thereby activates the mesolimbic dopaminergic neurons.
SCH 32615是一种新型的中性内肽酶（NEP，E.C. 3.4.24.11）抑制剂，即所谓的“脑啡肽酶”，它在[Met5]-和[Leu5]脑啡肽的降解过程中发挥作用。本研究旨在评估SCH 32615是否能够改变多巴胺能神经元的活性，这可通过大鼠脑三个不同区域（伏隔核、纹状体和前额叶皮质）中主要多巴胺代谢产物二羟基苯乙酸（DOPAC）含量的变化来反映。当以镇痛活性剂量（1 - 100 mg/kg皮下注射，处死前60分钟）给药时，SCH 32615可使伏隔核中的多巴胺代谢呈剂量依赖性增加，但对纹状体和前额叶皮质无效。这种效应似乎是通过阿片受体介导的，因为纳洛酮（5 mg/kg皮下注射）可完全阻断该效应。足部电击引起的前额叶皮质中DOPAC含量的增加不受SCH 32615预处理的影响。在伏隔核中，足部电击和单独给予的SCH 32615均可使多巴胺代谢增加至相同程度，但这些效应并非相加的，这表明SCH 32615和足部电击通过共同机制起作用。综上所述，这些结果支持以下假设：全身给予SCH 32615诱导的脑啡肽体内降解抑制增加了中枢神经系统中的脑啡肽能张力，从而激活了中脑边缘多巴胺能神经元。
