Waksman G, Hamel E, Delay-Goyet P, Roques B P
Département de Chimie Organique, U 266 I.N.S.E.R.M., UA 498 C.N.R.S., Faculté de Pharmacie, Paris, France.
Brain Res. 1987 Dec 15;436(2):205-16. doi: 10.1016/0006-8993(87)91663-5.
The cellular localization of the rat brain neutral endopeptidase (NEP, EC 3.4.24.11) was investigated by quantitative autoradiography of the enzyme inhibitor [3H]N-[(2RS)-3-hydroxyaminocarbonyl-2-benzyl-1-oxopropyl]glycine ([3H]HACBO-Gly) after lesions of the striatum, nigrostriatal and corticostriatal pathways. The effect of these lesions on NEP levels was compared with that on delta and mu opioid receptors, selectively labeled with [3H]Tyr-D-Thr-Gly-Leu-Thr ([3H]DTLET) and [3H]Tyr-D-Ala-Gly-MePhe-Glycinol ([3H]DAGO), respectively. Twenty-one days after injection of kainate in the caudate putamen (CP), the NEP level was locally decreased (52%) but the time course of this decrease was different from that of mu and delta opioid receptors: [3H]DAGO binding was diminished by 40% from day 2 whereas that of [3H]DTLET was reduced by 51% from day 7. Kainic acid injection in the CP induced in the globus pallidus (GP) and substantia nigra (SN) a distant reduction of the 3 opioid markers. Likewise after injection of colchicine in the CP, [3H]HACBO-Gly binding was decreased in the GP (60%) and SN (58%), [3H]DTLET binding was reduced by 54 and 55% in the GP and SN, respectively and [3H]DAGO labeling was diminished by 49% in the GP, and 58% in the SN. Finally, lesion of the nigrostriatal dopamine pathway by 6-hydroxydopamine did not induce any change of NEP level in the CP and GP whereas delta and mu opioid receptor levels were diminished respectively by 25 and 29% in the CP, and 45 and 39% in the GP, a new finding of the present study. Taken together these data suggest that NEP is in part associated with striatal intrinsic neurons. In the GP and SN, a large part of NEP seems to be presynaptically associated with nerve terminals endowed with mu and delta opioid receptors, which originate from efferent striatal neurons. In contrast to opioid receptors in the CP, the NEP appears not to be associated with dopaminergic nerve terminals originating from the SN. Cortical ablation did not affect any of the opioid markers.
通过对纹状体、黑质纹状体和皮质纹状体通路损伤后，利用酶抑制剂[3H]N-[(2RS)-3-羟基氨基羰基-2-苄基-1-氧代丙基]甘氨酸（[3H]HACBO-Gly）进行定量放射自显影，研究大鼠脑中性内肽酶（NEP，EC 3.4.24.11）的细胞定位。将这些损伤对NEP水平的影响与对δ和μ阿片受体的影响进行比较，δ和μ阿片受体分别用[3H]Tyr-D-Thr-Gly-Leu-Thr（[3H]DTLET）和[3H]Tyr-D-Ala-Gly-MePhe-Glycinol（[3H]DAGO）选择性标记。在尾状核壳核（CP）注射海藻酸21天后，NEP水平局部降低（52%），但其降低的时间进程与μ和δ阿片受体不同：[3H]DAGO结合从第2天开始减少40%，而[3H]DTLET结合从第7天开始减少51%。在CP注射海藻酸可导致苍白球（GP）和黑质（SN）中3种阿片标记物的远距离减少。同样，在CP注射秋水仙碱后，[3H]HACBO-Gly结合在GP（60%）和SN（58%）中降低，[3H]DTLET结合在GP和SN中分别减少54%和55%，[3H]DAGO标记在GP中减少49%，在SN中减少58%。最后，6-羟基多巴胺损伤黑质纹状体多巴胺通路并未诱导CP和GP中NEP水平发生任何变化，而CP中δ和μ阿片受体水平分别降低25%和29%，GP中分别降低45%和39%，这是本研究的一项新发现。综合这些数据表明，NEP部分与纹状体内在神经元相关。在GP和SN中，大部分NEP似乎在突触前与具有μ和δ阿片受体的神经末梢相关，这些神经末梢起源于纹状体传出神经元。与CP中的阿片受体不同，NEP似乎与起源于SN的多巴胺能神经末梢无关。皮质切除未影响任何阿片标记物。
