PDF(Pubmed)
Abstract：
Alcohol consumption is associated with gut dysbiosis, increased intestinal permeability, endotoxemia, and a cascade that leads to persistent systemic inflammation, alcoholic liver disease, and other ailments. Craving for alcohol and its consequences depends, among other things, on the endocannabinoid system. We have analyzed the relative role of central vs. peripheral cannabinoid CB1 receptors (CB1R) using a \"two-bottle\" as well as a \"drinking in the dark\" paradigm in mice. The globally acting CB1R antagonist rimonabant and the non-brain penetrant CB1R antagonist JD5037 inhibited voluntary alcohol intake upon systemic but not upon intracerebroventricular administration in doses that elicited anxiogenic-like behavior and blocked CB1R-induced hypothermia and catalepsy. The peripherally restricted hybrid CB1R antagonist/iNOS inhibitor S-MRI-1867 was also effective in reducing alcohol consumption after oral gavage, while its R enantiomer (CB1R inactive/iNOS inhibitor) was not. The two MRI-1867 enantiomers were equally effective in inhibiting an alcohol-induced increase in portal blood endotoxin concentration that was caused by increased gut permeability. We conclude that (i) activation of peripheral CB1R plays a dominant role in promoting alcohol intake and (ii) the iNOS inhibitory function of MRI-1867 helps in mitigating the alcohol-induced increase in endotoxemia.
摘要：
饮酒与肠道菌群失调有关，肠道通透性增加，内毒素血症,以及导致持续性全身炎症的级联反应，酒精性肝病,和其他疾病。对酒精的渴望及其后果取决于，除其他外，内源性大麻素系统。我们分析了中央与中央的相对作用。在小鼠中使用“两瓶”和“黑暗中饮酒”范式的外周大麻素CB1受体（CB1R）。全球作用的CB1R拮抗剂利莫那班和非脑渗透剂CB1R拮抗剂JD5037在全身注射时抑制自愿饮酒，但在脑室内注射时不会引起焦虑样行为并阻断CB1R诱导的体温过低和僵直。外周限制性杂合CB1R拮抗剂/iNOS抑制剂S-MRI-1867也可有效减少口服灌胃后的饮酒量，而其R对映体（CB1R无活性/iNOS抑制剂）则没有。两种MRI-1867对映异构体在抑制由肠通透性增加引起的酒精诱导的门静脉血内毒素浓度增加方面同样有效。我们得出的结论是，（i）外周CB1R的激活在促进酒精摄入中起着主导作用，（ii）MRI-1867的iNOS抑制功能有助于减轻酒精引起的内毒素血症增加。
