Ou Xiao-Ming, Udemgba Chinelo, Wang Niping, Dai Xiaoli, Lomberk Gwen, Seo Seungmae, Urrutia Raul, Wang Junming, Duncan Jeremy, Harris Sharonda, Fairbanks Carolyn A, Zhang Xiao
Department of Psychiatry and Human Behavior , University of Mississippi Medical Center, Jackson, Mississippi.
Alcohol Clin Exp Res. 2014 Feb;38(2):401-8. doi: 10.1111/acer.12258. Epub 2014 Jan 15.
Alcohol (EtOH [ethanol]) is an antinociceptive agent, working in part, by reducing sensitivity to painful stimuli. The transcription factor Kruppel-like factor 11 (KLF11), a human diabetes-causing gene that also regulates the neurotransmitter metabolic enzymes monoamine oxidase (MAO), has recently been identified as an EtOH-inducible gene. However, its role in antinociception remains unknown. Consequently, we investigated the function of KLF11 in chronic EtOH-induced antinociception using a genetically engineered knockout mouse model.
Wild-type (Klf11(+/+) ) and KLF11 knockout (Klf11(-/-) ) mice were fed a liquid diet containing EtOH for 28 days with increasing amounts of EtOH from 0% up to a final concentration of 6.4%, representing a final diet containing 36% of calories primarily from EtOH. Control mice from both genotypes were fed liquid diet without EtOH for 28 days. The EtOH-induced antinociceptive effect was determined using the tail-flick test before and after EtOH exposure (on day 29). In addition, the enzyme activity and mRNA levels of MAO A and MAO B were measured by real-time RT-PCR and enzyme assays, respectively.
EtOH produced an antinociceptive response to thermal pain in Klf11(+/+) mice, as expected. In contrast, deletion of KLF11 in the Klf11(-/-) mice abolished the EtOH-induced antinociceptive effect. The mRNA and protein levels of KLF11 were significantly increased in the brain prefrontal cortex of Klf11(+/+) mice exposed to EtOH compared with control Klf11(+/+) mice. Furthermore, MAO enzyme activities were affected differently in Klf11 wild-type versus Klf11 knockout mice exposed to chronic EtOH. Chronic EtOH intake significantly increased MAO B activity in Klf11(+/+) mice.
The data show KLF11 modulation of EtOH-induced antinociception. The KLF11-targeted MAO B enzyme may contribute more significantly to EtOH-induced antinociception. Thus, this study revealed a new role for the KLF11 gene in the mechanisms underlying the antinociceptive effects of chronic EtOH exposure.
酒精（乙醇，EtOH）是一种抗伤害感受剂，其部分作用机制是降低对疼痛刺激的敏感性。转录因子Kruppel样因子11（KLF11）是一种可导致人类患糖尿病的基因，同时也调节神经递质代谢酶单胺氧化酶（MAO），最近被鉴定为一种乙醇诱导基因。然而，其在抗伤害感受中的作用尚不清楚。因此，我们使用基因工程敲除小鼠模型研究了KLF11在慢性乙醇诱导的抗伤害感受中的功能。
野生型（Klf11(+/+)）和KLF11敲除（Klf11(-/-)）小鼠喂食含乙醇的液体饲料28天，乙醇含量从0%逐渐增加至最终浓度6.4%，即最终饲料中36%的热量主要来自乙醇。两种基因型的对照小鼠喂食不含乙醇的液体饲料28天。在乙醇暴露前后（第29天），使用甩尾试验测定乙醇诱导的抗伤害感受作用。此外，分别通过实时逆转录聚合酶链反应和酶测定法测量MAO A和MAO B的酶活性和mRNA水平。
正如预期的那样，乙醇在Klf11(+/+)小鼠中产生了对热痛的抗伤害感受反应。相比之下，Klf11(-/-)小鼠中KLF11的缺失消除了乙醇诱导的抗伤害感受作用。与对照Klf11(+/+)小鼠相比，暴露于乙醇的Klf11(+/+)小鼠脑前额叶皮质中KLF11的mRNA和蛋白质水平显著增加。此外，在暴露于慢性乙醇的Klf11野生型小鼠与Klf11敲除小鼠中，MAO酶活性受到的影响不同。慢性乙醇摄入显著增加了Klf11(+/+)小鼠中的MAO B活性。
数据显示KLF11对乙醇诱导的抗伤害感受具有调节作用。靶向KLF11的MAO B酶可能对乙醇诱导的抗伤害感受贡献更大。因此，本研究揭示了KLF11基因在慢性乙醇暴露抗伤害感受作用机制中的新作用。
