Murillo-Rodríguez Eric, Vázquez Edgar, Millán-Aldaco Diana, Palomero-Rivero Marcela, Drucker-Colin René
Depto de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, México.
Eur J Pharmacol. 2007 May 7;562(1-2):82-91. doi: 10.1016/j.ejphar.2007.01.076. Epub 2007 Feb 8.
Our group has described previously that the endogenous cannabinoid anandamide induces sleep. The hydrolysis of this lipid involves the activity of the fatty acid amide hydrolase (FAAH), which additionally catalyzes the degradation of the satiety factor oleoylethanolamide and the analgesic-inducing lipid palmitoylethanolamide. It has been demonstrated that the inhibition of the FAAH by URB597 increases levels of anandamide, oleoylethanolamide and palmitoylethanolamide in the brain of rats. In order to determinate the physiological properties of the FAAH inhibition on the sleep modulation, we report the pharmacological effects on the sleep-wake cycle of the rat after i.c.v. administrations of URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl). Separate unilateral i.c.v. injections of 3 compounds during the lights-on period, increased wakefulness and decreased slow wave (SW) sleep in rats in a dose-dependent fashion. We additionally found out that, compared to controls, c-Fos immunoreactivity in hypothalamus and dorsal raphe nucleus was increased in rats that received URB597, oleoylethanolamide or palmitoylethanolamide (10, 20 microg/5 microl, i.c.v.). Next, we found that after an injection of the compounds, levels of dopamine were increased whereas extracellular levels of levodopa (l-DOPA) were decreased. These findings indicate that that inhibition of the FAAH, via URB597, modulates waking. These effects were mimicked separately by the administration of oleoylethanolamide or palmitoylethanolamide. The alertness induced by the compounds tested here activated wake-promoting brain regions and they also induced the release of dopamine. Our results suggest that FAAH activity as well as two molecules that are catalyzed by this enzyme, oleoylethanolamide and palmitoylethanolamide, participate in the regulation of the waking state. Alternative approaches to treat sleep disorders such as excessive somnolence might consider the use of the URB597, oleoylethanolamide or palmitoylethanolamide since all compounds enhance waking.
我们团队之前曾描述过内源性大麻素花生四烯酸乙醇胺可诱导睡眠。这种脂质的水解涉及脂肪酸酰胺水解酶（FAAH）的活性，该酶还催化饱腹感因子油酰乙醇胺和镇痛诱导脂质棕榈酰乙醇胺的降解。已证明，URB597对FAAH的抑制作用可提高大鼠脑中花生四烯酸乙醇胺、油酰乙醇胺和棕榈酰乙醇胺的水平。为了确定FAAH抑制对睡眠调节的生理特性，我们报告了经脑室内注射URB597、油酰乙醇胺或棕榈酰乙醇胺（10、20微克/5微升）后对大鼠睡眠-觉醒周期的药理作用。在光照期间分别单侧脑室内注射这3种化合物，可使大鼠的觉醒增加，慢波（SW）睡眠减少，且呈剂量依赖性。我们还发现，与对照组相比，接受URB597、油酰乙醇胺或棕榈酰乙醇胺（10、20微克/5微升，脑室内注射）的大鼠下丘脑和中缝背核中的c-Fos免疫反应性增加。接下来，我们发现注射这些化合物后，多巴胺水平升高，而细胞外左旋多巴（l-DOPA）水平降低。这些发现表明，通过URB597抑制FAAH可调节觉醒。油酰乙醇胺或棕榈酰乙醇胺的给药分别模拟了这些作用。此处测试的化合物所诱导的警觉性激活了促进觉醒的脑区，并且它们还诱导了多巴胺的释放。我们的结果表明，FAAH活性以及该酶催化的两种分子，即油酰乙醇胺和棕榈酰乙醇胺，参与了觉醒状态的调节。治疗睡眠障碍如过度嗜睡的替代方法可能会考虑使用URB597、油酰乙醇胺或棕榈酰乙醇胺，因为所有这些化合物均可增强觉醒。
