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.