| Opioid addiction, commonly known as "drug taking", has become a global public problem which not only harms abusers’ health but also induces a serial social, economical and public health problems. However, there is no effective medicine to treat replase. Because the mechanism is complicated and unclear. In the future, the perfect target and medicine has no abuse liability itself and inihibit relapse.Our previous research showed that agmatine itself had no abuse liability and could relieve withdrawl syndrome and attaneuate opioid dependence. The target of agmitine was conjectured to I1 imidazoline receptor(I1R). In vitro and vivo studies, the effect of agmatine mediated by I1 R may be a novel system to regulate opioid addiction. However, there is no evidence to confirm the effect of agmatine to treat opioid addiction mediated by I1 R in vivo, because there is no selectivity with ???-AR, NMDA receptor, voltage-gated calcium channels and NOS which are also targets for opioid addiction. Our previous research constructed the IRAS(imidazoline receptor antisera selected protein) gene knockout mice to provide animal models to study the mechanisms of I1 R for opioid addiction. Therefore, the project investigated the regulation of I1 R in opioid addiction and the effect of agmitine –I1R. These findings were listed as follows:(A) The regulation of I1 R in opioid psychological dependence.(1) Self-administration is a classic addiction animal model which can imitate the progress of human addiction, displaying the process of acquisition, maintenance, withdrawal and relapse. It is the most test-valid model to investigate the mechanisms of addiction.In heroin(0.025 mg/kg/infusion, i.v.)-induced self-administration model, the infusions in I1R-/- mice was significantly higher than that in wild type mice under FR1 procedure. In dose-response curve of heroin, the curve shifted to upper in I1R-/- mice. It suggested that the effect of heroin was enhanced in I1R-/- mice. The behaviors of taking drug(active poses) and drug-intake was significantly higher in I1R-/- mice. These results suggest that the positive reinforcement effect of heroin was enhanced in I1R-/- mice. We firstly found that I1 R may play a negative role in regulating heroin addiction.(2) In the locomotion models, there is no different between I1R-/- mice and wild type mice. In the mophine-induced hyperlocomotion, morphine(5, 10 mg/kg, s.c.) could not induce hyperlocomotion in I1R-/- mice. In the morphine-induced behavior sensitization model, morphine(5, 10 mg/kg, s.c.) could induce behavioral sensitization significantly in wild type mice, while failed in I1R-/- mice. Based on the results, they were conflict with results of heroin-induced self-administration. The reason is still unclear and deserved to study.In conclusion, the downregulation of I1 R enhanced the sensitivity to opiate addiction in heroin induced self-administration, which was consistent with earlier results that agmatine inhibited opioid addiction which is probably by activating I1 R.(B) At the same time, we built the neuronal specific knockdown I1 R mice to improve the specificities of results. Psychic behavior and basal physiology were tested in I1 R neuron-specific knockout mice.(1) In the sucrose(5%, w/v)-induced self-administration experiment, there was no significantly difference between I1R-/- neuron mice and wild-type mice. It suggested that there was no effect on natural reward in I1R-/- neuron mice.(2) In the hot plate test, which determined the basal pain threshold, showed that the pain threshold was reduced after deleting neuronal I1 R. It suggested that the neuronal I1 R may be involved in the regulation of pain. This result was agree with prior outcomes that agmatine had slight effect on analgesia by activating I1 R.(3) The serial doses of morphine(4, 8 and 16 mg/kg, s.c.) could significantly increase the locomotor activity and there was no significantly difference between the two types.The results mentioned above indicated that neuron-specific delete I1 R had no effect on natural rewards, and neuronal I1 R may inhibit threshold of pain while agmatine had slight analgesia effect, by enhancing morphine analgesia and inhibiting the development of morphine induced physical dependence. So I1 R in neuron may be involved in the regulation of opioid addiction. Specific knockout of I1 R in neurons have no effect to high doses of morphine induced hyperlocomotion, and the investigation of whether neuronal I1 R take part in the modulation of opioid addiction is ongoing.(C) Experimental animals were mice in this study, while prior experimental animals were rats in studying the pharmacodynamic role of agmatine on inhibiting opioid psychological dependence, so we observed the role of agmatine in morphine-induced behavioral sensitization in C57BL/6J mice before gaining enough knockout mice and wide type mice to make phenotypic analysis.(1) Pretreatment with agmatine(1-80 mg/kg, s.c.) had no effect on both locomotor activity and hyperlocomotion induced by acute morphine(10 mg/kg, s.c.)in mice. Agmatine at high doses(80 mg/kg, s.c.) had a weak inhibition in morphine(10 mg/kg, s.c.)induced behavioral sensitization with no significant difference.(2) Single dose of yohimbine(2 mg/kg, i.p.), the selective antagonist?of??2-adrenoceptor(?2-AR), had no effect on both locomotor activity and hyperlocomotion induced by morphine. Co-administration of yohimbine(2 mg/kg, i.p.) and agmatine(80 mg/kg, s.c.) can significantly reduce hyperlocomotion induced by acute morphine administration and the development of behavioral sensitization. It suggested that activating I1 R by agmatine and blocking ?2-AR by yohimbine can inhibit the positive reinforcement effect of morphine.In conclusion, agmatine atteuated opioid addiction in mice, which was not in consisitant with the results in rats. It needs more investigation for whether agmatine plays a role by activating I1 R in knockout mice.In summary, I1R-/- enhanced the sensitivity to opiate addiction, which was consistent with the role of agmatine on opioid addiction. Neuronal I1R-/- had no effect on the natural reward. It decreased the pain threshold in mice, and was agree with the weak analgesic of agmatine by activating I1 R. The combination of agmatine and yohimbine played a role on inhibiting opioid addiction in wild-type mice. It suggested that agmatine-I1 R system, a new regulation system about opioid functional, may be an ideal drug target for opioid addiction. |
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