Alterations within the endogenous opioid system in mice with targeted deletion of the neutral endopeptidase ('enkephalinase') gene
Alterations within the endogenous opioid system in mice with targeted deletion of the neutral endopeptidase ('enkephalinase') gene
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DOI：
10.1016/s0167-0115(00)00200-7
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发表时间：
2000-12-22
影响因子：
--
通讯作者：
Saria, A
中科院分区：
文献类型：
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作者：
Fischer, HS;Zernig, G;Saria, A
中性内肽酶（enkephalinase，NEP，EC3.4.24.11）对脑啡肽的生物失活代表了脑啡肽能信号传导终止的主要机制。NEP活性的药理学阻断增强细胞外脑啡肽浓度并诱导阿片依赖性镇痛。最近，已经开发了缺乏酶NEP的基因敲除小鼠[Lu等人，J. Exp. 1995;181：2271-2275]。本研究调查的功能后果和生化补偿策略的NEP活动的系统消除这些基因敲除小鼠。使用生化和行为测试，我们发现，缺乏NEP的活动在大脑中并没有得到补偿的替代脑啡肽降解酶的活性增强。与野生型相比，通过原位方法定量NEP缺陷小鼠纹状体前脑啡肽原mRNA水平，也未检测到脑啡肽生物合成的变化。在NEP敲除小鼠的粗脑匀浆中，仅观察到μ受体密度降低21%，而δ-和κ-阿片受体密度不变。这种受体下调也证实了在功能上的热板范例。NEP敲除正常发展，但在居民入侵者的范例中表现出增强的攻击行为，并改变了在光束系统中评估的自发活动。因此，尽管NEP在脑啡肽能神经传递中起重要作用。NEP缺陷小鼠的阿片样物质系统内的生物化学适应仅具有适度的性质。(C)2000 Elsevier Science B. V.保留所有权利。
The biological inactivation of enkephalins by neutral endopeptidase (enkephalinase, NEP, EC3.4.24.11) represents a major mechanism for the termination of enkephalinergic signalling in brain. A pharmacological blockade of NEP-activity enhances extracellular enkephalin concentrations and induces opioid-dependent analgesia. Recently, knockout mice lacking the enzyme NEP have been developed [Lu et al., J. Exp. Med. 1995;181:2271-2275]. The present study investigates the functional consequences and biochemical compensatory strategies of a systemic elimination of NEP activity in these knockout mice. Using biochemical and behavioural tests we found that the lack of NEP activity in brain is not compensated by enhanced activities of alternative enkephalin-degrading enzymes. Also no change in enkephalin biosynthesis was detectable by in situ methods quantifying striatal proenkephalin-mRNA levels in NEP-deficient mice compared with wildtype. Only a 21% reduction of mu receptor density in crude brain homogenates of NEP knockout mice was observed, while delta- and kappa -opioid receptor densities were unchanged. This receptor downregulation was also confirmed functionally in the hot-plate paradigm. NEP knockouts developed normally, but showed enhanced aggressive behaviour in the resident-intruder paradigm, and altered locomotor activity as assessed in the photobeam system. Thus, although NEP plays a substantial role in enkephalinergic neurotransmission. the biochemical adaptations within the opioid system of NEP-deficient mice are of only modest nature. (C) 2000 Elsevier Science B.V. All rights reserved.