Department of Pharmacology, Third Faculty of Medicine, Charles University, Ruska 87, Prague 10, 100 34, Czech Republic.
Department of Addictology, First Faculty of Medicine, Charles University, Apolinarska 4, Prague 2, Czech Republic.
Neurochem Int. 2017 Nov;110:101-113. doi: 10.1016/j.neuint.2017.09.013. Epub 2017 Sep 27.
An increasing number of studies over the past few years have demonstrated ghrelin's role in alcohol, cocaine and nicotine abuse. However, the role of ghrelin in opioid effects has rarely been examined. Recently we substantiated in rats that ghrelin growth hormone secretagogue receptors (GHS-R1A) appear to be involved in acute opioid-induced changes in the mesolimbic dopaminergic system associated with the reward processing. The aim of the present study was to ascertain whether a ghrelin antagonist (JMV2959) was able to inhibit morphine-induced biased conditioned place preference and challenge-morphine-induced accumbens dopaminergic sensitization and behavioral sensitization in adult male rats. In the place preference model, the rats were conditioned for 8 days with morphine (10 mg/kg s.c.). On the experimental day, JMV2959 (3 and 6 mg/kg i.p.) or saline were administered before testing. We used in vivo microdialysis to determine changes of dopamine and its metabolites in the nucleus accumbens in rats following challenge-morphine dose (5 mg/kg s.c.) with or without JMV2959 (3 and 6 mg/kg i.p.) pretreatment, administered on the 12th day of spontaneous abstinence from morphine repeated treatment (5 days, 10-40 mg/kg). Induced behavioral changes were simultaneously monitored. Pretreatment with JMV2959 significantly and dose dependently reduced the morphine-induced conditioned place preference and significantly and dose dependently reduced the challenge-morphine-induced dopaminergic sensitization and affected concentration of by-products associated with dopamine metabolism in the nucleus accumbens. JMV2959 pretreatment also significantly reduced challenge-morphine-induced behavioral sensitization. Our present data suggest that GHS-R1A antagonists deserve to be further investigated as a novel treatment strategy for opioid addiction.
在过去的几年中，越来越多的研究表明 ghrelin 在酒精、可卡因和尼古丁滥用中的作用。然而，ghrelin 在阿片类药物效应中的作用很少被研究过。最近，我们在大鼠中证实，ghrelin 生长激素促分泌受体（GHS-R1A）似乎参与了急性阿片类药物诱导的与奖励处理相关的中脑边缘多巴胺能系统的变化。本研究的目的是确定 ghrelin 拮抗剂（JMV2959）是否能够抑制吗啡诱导的偏置条件性位置偏好以及挑战吗啡诱导的伏隔核多巴胺敏化和行为敏化在成年雄性大鼠中。在位置偏好模型中，大鼠用吗啡（10mg/kg sc）进行 8 天的条件训练。在实验日，JMV2959（3 和 6mg/kg ip）或生理盐水在测试前给予。我们使用体内微透析来确定在挑战吗啡剂量（5mg/kg sc）后大鼠伏隔核中多巴胺及其代谢物的变化，以及 JMV2959（3 和 6mg/kg ip）预处理，在吗啡重复治疗（5 天，10-40mg/kg）自发戒断的第 12 天给予。同时监测诱导的行为变化。JMV2959 预处理显著且剂量依赖性地降低了吗啡诱导的条件性位置偏好，显著且剂量依赖性地降低了挑战吗啡诱导的多巴胺敏化，并影响了伏隔核中与多巴胺代谢相关的副产物的浓度。JMV2959 预处理还显著降低了挑战吗啡诱导的行为敏化。我们目前的数据表明，GHS-R1A 拮抗剂值得进一步研究，作为阿片类药物成瘾的一种新的治疗策略。
