Alterations within the endogenous opioid system in mice with targeted deletion of the neutral endopeptidase ('enkephalinase') gene

被引:23
作者
Fischer, HS
Zernig, G
Schuligoi, R
Miczek, KA
Hauser, KF
Gerard, C
Saria, A [1 ]
机构
[1] Univ Innsbruck, Dept Psychiat, Div Neurochem, A-6020 Innsbruck, Austria
[2] Graz Univ, Dept Expt & Clin Pharmacol, A-8010 Graz, Austria
[3] Tufts Univ, Medford, MA 02155 USA
[4] Univ Kentucky, Coll Med, Dept Anat & Neurobiol, Lexington, KY 40536 USA
[5] Harvard Univ, Sch Med, Dept Pediat Med, Boston, MA USA
[6] Childrens Hosp, Boston, MA 02115 USA
关键词
EC; 3.4.24.11; enkephalinase; knockout; mice;
D O I
10.1016/S0167-0115(00)00200-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:53 / 58
页数:6
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