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Sigma receptor-induced heavy drinking in rats: Modulation by the opioid receptor system.
Pharmacology Biochemistry and Behavior ( IF 3.6 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.pbb.2020.172914
Marta Valenza 1 , Angelo Blasio 1 , Alyssa DiLeo 2 , Pietro Cottone 1 , Valentina Sabino 1
Affiliation  

Alcohol use disorder (AUD) is a major cause of morbidity and mortality worldwide, for which new efficacious treatments are necessary. The opioid receptor system is a mediator of the rewarding effects of alcohol; in particular, while activation of μ opioid receptors enhances ethanol intake in rodents, opioid-receptor antagonists, such as naloxone and naltrexone, reduce its pleasurable and reinforcing effects, thereby decreasing alcohol. Sigma receptors (Sig-Rs) have been proposed as modulators of the effects of alcohol and, therefore, as a potential new pharmacological target for AUD. Somewhat analogously to μ opioid ligands, SigR agonists increase, while SigR antagonists decrease alcohol intake in animal models of excessive alcohol drinking. However, a potential cross-talk between these two receptor systems in relation to alcohol consumption has so far not been investigated. Here, we addressed this question pharmacologically, by testing the effects of either activating or inhibiting opioid receptors on the heavy alcohol drinking induced by chronic stimulation of SigR in alcohol-preferring rats. We found that the opioid receptor agonist morphine, which per se increases ethanol intake, at a sub-threshold dose reduces the binge-like drinking induced by the repeated treatment with the SigR agonist 1,3-di-o-tolylguanidine (DTG); conversely, the opioid receptor antagonist naltrexone, which per se reduces ethanol intake, at a sub-threshold dose potentiates the DTG-induced binge-like drinking. Our data show a cross-talk between the opioid and SigR systems relevant to the modulation of alcohol drinking, which provides important insights into the neurobiology of AUD and may lead to the development of novel therapies, either standalone or in combination.



中文翻译:

Sigma 受体诱导的大鼠大量饮酒:阿片受体系统的调节。

酒精使用障碍 (AUD) 是全球发病率和死亡率的主要原因,因此需要新的有效治疗方法。阿片受体系统是酒精奖赏作用的中介;特别是,虽然 μ 阿片受体的激活会增加啮齿动物的乙醇摄入量,但阿片受体拮抗剂(例如纳洛酮和纳曲酮)会降低其令人愉悦和增强的作用,从而减少酒精。Sigma 受体 (Sig-Rs) 已被提议作为酒精作用的调节剂,因此,作为 AUD 的潜在新药理学靶点。与μ阿片配体有些类似,SigR 激动剂增加,而 SigR 拮抗剂减少过度饮酒动物模型中的酒精摄入量。然而,迄今为止,尚未研究这两种受体系统之间与饮酒有关的潜在串扰。在这里,我们通过测试激活或抑制阿片受体对嗜酒大鼠长期刺激 SigR 诱导的重度饮酒的影响,从药理学上解决了这个问题。我们发现阿片受体激动剂吗啡本身增加乙醇摄入量,低于阈值剂量可减少由 SigR 激动剂 1,3-二--甲苯基胍 (DTG) 重复处理引起的暴饮暴食;相反,阿片受体拮抗剂纳曲酮本身可减少乙醇摄入量,在亚阈值剂量下会增强 DTG 诱导的暴饮暴食。我们的数据显示阿片类药物和 SigR 系统之间与饮酒调节相关的交叉对话,这为 AUD 的神经生物学提供了重要的见解,并可能导致新疗法的发展,无论是单独的还是组合的。

更新日期:2020-03-20
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