| Background:Drug addiction,known as drug dependence,is a chronic relapsing encephalopathy characterized by compulsive drug use,drug foraging,and high relapse rates,which has caused serious harm to society.Ketamine(KET)has pharmacological effects of anesthesia and analgesia,antiaddiction and antidepressant,but its clinical application is limited by its hallucinogenic and addictive adverse effects.Previous studies have suggested that ketamine addiction is mainly related to N-methyl-D-aspartic acid(NMDA)receptors,but existing studies suggest that opioid receptors may play an important role in ketamine addiction.Currently,there are no effective biomedical tools to counteract ketamine addiction because the mechanisms of ketamine addiction are not well understood.Therefore,the development of drugs that can treat ketamine addiction is a necessary and meaningful task.Thienorphine(Thien)is used as an opioid receptor partial agonist that activates κ-opioid receptor(KOR)and δ-opioid receptor(DOR),and partially activates μ-opioid receptor(MOR).It has a low activation effect on the orphan opioid receptor(NOPR).Thienorphine has analgesic effects and can counteract morphine relapse,and is currently in phase II clinical studies as a morphine relapse prevention drug.There are no reports on whether thienorphine against other types of addictive substances other than morphine.Objective:The aim of this project is to clarify the effect of thienorphine against ketamine addiction,to elucidate the role of opioid receptors in ketamine addiction,to provide reference for revealing the mechanism of action of ketamine addiction,and to provide effective drug candidates for solving ketamine addiction.Methods:(1)The development of thienorphine against ketamine-induce addictionThienorphine against the development of ketamine psychiatric dependence:(1)The effect of thienorphine on ketamine-induced hyperspontaneous activity.C57BL/6J mice were administering Thien subcutaneously and KET was administered intraperitoneally 30 min later to test the spontaneous activity of mice within 30 min.In order to verify whether a single administration of Thien affects the locomotor activity of mice,C57BL/6J mice were given Thien subcutaneously and locomotor activity was tested within30 min.(2)The effect of thienorphine on the development of ketamine-induced behavioral sensitization.Thien was given subcutaneously to C57BL/6J mice and KET was given intraperitoneally 30 min later for 5 days;5 days of withdrawal;on day 11,each group of mice was given KET to stimulate,the locomotor activities of mice were tested on days 1,5and 11.In order to verify whether multiple administration of thienorphine induces the development of behavioral sensitization,C57BL/6J mice were given Thien subcutaneously once a day for 7 days;withdrawal for 7 days;each group of mice was given thienorphine to stimulate,on day 15,locomotor activity was tested on days 1,4,7,and 15.Thienorphine against the development of ketamine somatic dependence:(1)The effect of thienorphine against acute withdrawal of ketamine.Thien was given subcutaneously to C57BL/6J mice and KET was given intraperitoneally 30 min later,the procedure was repeated on day 2 and NMDA was given in the lateral ventricle on day 3 to induce withdrawal.(2)The effect of thienorphine against chronic withdrawal of ketamine.KET was administered intraperitoneally to C57BL/6J mice three times a day for 10 days according to the principle of increasing dose day by day,Thien was given subcutaneously 30 min before the first daily ketamine administration,NMDA was given in the lateral ventricle on day 11 to induce withdrawal.(2)Reconstruction of thienorphine-resistant ketamine addiction behavior(1)The effect of thienorphine on the transfer of ketamine-induced behavioral sensitization.C57BL/6J mice were given KET intraperitoneally for 5 consecutive days;Thien was given subcutaneously on days 6 ～ 10;on day 11,each group of mice was given KET stimulate,and the locomotor activities of mice were tested on days 1,5 and 11.(2)The effect of thienorphine on the expression of ketamine-induced behavioral sensitization.C57BL/6J mice were given KET intraperitoneally for 5 days;withdrawal 5days;on day 11,Thien was given subcutaneously and 30 min later KET was administered for stimulation,the locomotor activity of the mice was tested on days 1,5 and 11,respectively.(3)The effect of opioid receptors in ketamine addiction mechanismRole of MOR in the mechanism of ketamine addiction:(1)The effect of MOR knockout on spontaneous activity of ketamine-induced.MOR knockout/wild-type mice were given KET intraperitoneally and spontaneous activity of the mice was tested within 30 min.(2)The effect of MOR knockout on the development of ketamine-induced behavioral sensitization.MOR knockout/wild-type mice were given KET intraperitoneally once a day for 5 days;5 days of withdrawal;on day 11,each group of mice was given KET to stimulate,locomotor activities of mice were tested on days 1,5,and 11,respectively.Role of KOR in the mechanism of ketamine addiction.(1)The effect of KOR antagonists against ketamine-induced hyperspontaneous activity.C57BL/6J mice were given the KOR antagonist nor-BNI intraperitoneally and KET intraperitoneally 30 min later,and the locomotor activity of the mice was tested within 30 min.To verify whether nor-BNI affects the locomotor activity of mice,mice were given nor-BNI intraperitoneally and spontaneous activity of mice was tested for 30 min.(2)The effect of KOR agonists against ketamine-induced hyperspontaneous activity.C57BL/6J mice were given KOR agonist U50488 in the lateral ventricle and KET intraperitoneally 30 min later,and the spontaneous activity of mice was tested within 30 min.Role of DOR in the mechanism of ketamine addiction.Role of DOR in the mechanism of ketamine addiction:The role of DOR antagonists against ketamine-induced hyperspontaneous activity.C57BL/6J mice were given the DOR antagonist Naltrindole intraperitoneally and KET intraperitoneally 30 min later to test the spontaneous activity of mice within 30 min.To verify whether Naltrindole affects the locomotor activity of mice,mice were given Naltrindole intraperitoneally and spontaneous activity was tested for 30 min.Role of NOPR in the mechanism of ketamine addiction:The role of NOPR antagonist against ketamine-induced high spontaneous activity.C57BL/6J mice were given NOPR antagonist J113397 intraperitoneally and KET intraperitoneally after 30 min to test the spontaneous activity of mice within 30 min.In order to verify whether J113397 affects the locomotor activity of mice,mice were given J113397 intraperitoneally and spontaneous activity of mice was tested for 30 min.Results:(1)The effect of thienorphine on thedevelopment of ketamine addictionThe effects of thienorphine on ketamine psychiatric dependence.(1)Thienorphine(0.2 ～ 5 mg/kg,s.c.)could inhibit the high spontaneous activity induced by KET and a single administration of Thien(0.008 ～ 0.2 mg/kg,s.c.)had no significant effect on the spontaneous activity in mice.(2)Thienorphine(0.04 mg/kg,s.c.)significantly inhibited the development of behavioral sensitization induced by KET and multiple administration of thienorphine(0.008～ 0.2 mg/kg,s.c.)did not induce the development of behavioral sensitization in mice.The effects of thienorphine on ketamine somatic dependence:(1)In acute somatic withdrawal experiments,thienorphine(0.04、0.2 mg/kg,s.c.)significantly inhibited the withdrawal symptoms of licking toes,scratching cheek,scratching ear of ketamine-induced.(2)In the chronic somatic withdrawal experiment,thienorphine(0.04、0.2 mg/kg,s.c.)significantly inhibited the withdrawal symptoms of licking toes,scratching cheek,scratching ear and grooming of ketamine-induced.(2)The effect of thienorphine on ketamine addiction reconstruction(1)Thienorphine(0.04、0.2 mg/kg,s.c.)had no significant effect on the transfer of KET induced behavioral sensitization.(2)Thienorphine(0.2 mg/kg,s.c.)significantly inhibited the expression of KET induced behavioral sensitization.(3)Role of opioid receptors in the mechanism of ketamine addiction(1)MOR knockdown had no effect on KET induced high spontaneous activity and the development of behavioral sensitization.(2)The KOR antagonist nor-BNI(50 mg/kg,i.p.)was able to inhibit KET induced high spontaneous activity and did not affect the locomotor activity of the mice itself.KOR agonist U50488(20 μg/5 μL,100 μg/5 μL,i.c.v.)had no significant effect on ketamineinduced high spontaneous activity.(3)The DOR antagonist naltrindole(1 ～ 25 mg/kg,i.p.)had no significant effect on ketamine-induced hyperspontaneous activity,and naltrindole itself did not affect the locomotor activity of mice.(4)NOPR antagonist J113397(1 ～ 25 mg/kg,i.p.)had no significant effect on ketamineinduced hyperspontaneous activity,and J113397 itself did not affect the locomotor activity of mice.Conclusion:(1)Thienorphine could inhibit acute and chronic somatic withdrawal symptoms induced by ketamine;thienorphine did not affect spontaneous activity in mice,but was able to inhibit ketamine-induced hyperspontaneous activity;thienorphine did not induce the development of behavioral sensitization,but was able to inhibit the development and expression of ketamine-induced behavioral sensitization,these results suggest that thienorphine has some intervention effects on ketamine addiction.(2)Ketamine addiction may be related to KOR and may not be related to MOR,DOR and NOPR.Innovation:(1)Thienorphine was found to have a counteracting effect on ketamine addiction.(2)Ketamine addiction mechanism was found to be related to κ opioid receptors... |
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