芋螺多肽conantokins及其类似物对小鼠吗啡戒断症状的抑制作用

目的:观察及评价NMDA受体抑制剂芋螺多肽conantokins及其类似物对吗啡依赖小鼠催促戒断症状的抑制作用。方法:采用剂量递增法皮下注射吗啡7d,建立吗啡依赖小鼠模型。观察conantokin及类似物con-G(2.5,5,10,15nmol·kg-1,icv),con-G[S16Y]〗(15nmol·kg-1,icv),con-R(1-17)(15,30nmol·kg-1,icv),对照药美金胺(46.3μmol·kg-1,ip)以及艾芬地尔(1.25μmo·lkg-1,icv;25μmol·kg-1,ip)对吗啡依赖小鼠纳洛酮催促戒断的跳跃次数及体重的影响。结果:与吗啡依赖组相比,icv15nmo·lkg-1con-G使吗啡依赖小鼠平均跳跃次数减少89.0%,并呈剂量依赖性(2.5-15nmo·lkg-1);icv15nmol·kg-1con-G[S16Y]〗可完全抑制吗啡依赖小鼠戒断跳跃。con-R(1-17)(15-30nmol·kg-1,icv)使吗啡依赖小鼠平均跳跃次数仅减少40.2%-58.3%。结论:con-G、con-G[S16Y]〗和con-R(1-17)对抑制小鼠的戒断症状非常有效。相对于con-R(1-17),con-G和con-G[S16Y]〗对小鼠的戒断症状的抑制作用更强,这是由于con-G、con-G[S16Y]〗对NMDA受体NR2B亚基的选择性更高。Conantokins及其类似物在抑制吗啡依赖方面很有潜力。

INHIBITORY EFFECTS OF CONANTOKINS AND VARIANTS ON WITHDRAWAL SYMPTOMS IN MORPHINE DEPENDENT MICE

Objective:To observe and assess the inhibitory effects of conantokins and the variants,NMDA receptor antagonists,on the withdrawal syndromes in morphine dependent mice.Methods: Mice were injected (sc) with morphine for 7 days according to an escalating dose schedule to induce physical dependence. The effects of con-G(2.5,5,10,15 nmol·kg~ -1 ,icv), con-GS~ 16 Y(15 nmol· kg~ -1 ,icv), con-R(1-17) (15,30 nmol·kg~ -1 ,icv),memantine (46.3 μmol·kg~ -1 ,ip) and ifenprodil (1.25 μmol·kg~ -1 ,icv;25 μmol·kg~ -1 , ip) on naloxone-induced jumping and body weight loss in morphine dependent mice were observed. Results:Con-G(15 nmol·kg~ -1 , icv) attenuated 89.0% of the naloxone-induced withdrawal jumping and showed a dose-dependent mode (2.5-15 nmol·kg~ -1 ). Con-GS~ 16 Y(15 nmol·kg~ -1 ,icv) could completely inhibit the withdrawal jumping. Con-R(1-17) (15-30 nmol·kg~ -1 , icv) just inhibited 40.2%-58.3% of the naloxone-induced withdrawal jumping. Conclusion:con-G,con-GS~ 16 Y and con-R(1-17) can significantly reduce morphine withdrawal symptoms. Compared with con-R(1-17),the higher inhibitory activities of con-G and con-GS~ 16 Y on naloxone-induced withdrawal jumping in morphine dependent mice arise from their higher selectivity of NR2B subunit of NMDA receptor. Conantokins have great potential in developing new candidate for inhibiting the development of morphine dependence.