Diabetes-Causing Gene, Kruppel-Like Factor 11, Modulates the Antinociceptive Response of Chronic Ethanol Intake

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2014-02, Vol.38 (2), p.401-408
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Alcoholism - genetics; Alcoholism - psychology; Analgesics; Animals; Antinociceptive Response; Blotting, Western; Central Nervous System Depressants - pharmacology; Chronic Ethanol Intake; Diabetes Mellitus - genetics; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Ethanol - pharmacology; Gene Knockout; Kruppel-Like Factor 11 (Transforming Growth Factor-Beta-Inducible Early Gene 2); Male; Mice; Mice, Knockout; Monoamine Oxidase; Monoamine Oxidase - genetics; Monoamine Oxidase - metabolism; Nociception - drug effects; Pain Measurement - drug effects; Prefrontal Cortex - drug effects; Prefrontal Cortex - enzymology; Reaction Time - drug effects; Real-Time Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Transcription Factors - biosynthesis; Transcription Factors - genetics; Transcription Factors - physiology
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.12258

Background 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. Methods 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. Results 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. Conclusions 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.