Influence of phenylmethylsulfonyl fluoride on anandamide brain levels and pharmacological effects.
Influence of phenylmethylsulfonyl fluoride on anandamide brain levels and pharmacological effects.
复制标题
苯甲基磺酰氟对 anandamide 脑水平和药理作用的影响。
DOI：
10.1016/s0024-3205(00)00749-9
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发表时间：
2000
期刊：
影响因子：
6.1
通讯作者：
Martin,BR
中科院分区：
文献类型：
--
作者：
Wiley,JL;Dewey,MA;Jefferson,RG;Winckler,RL;Bridgen,DT;Willoughby,KA;Martin,BR
内源性大麻素 anandamide 产生类似于 Δ9-四氢大麻酚 (Δ9-THC) 产生的大麻模拟作用，但由于其通过脂肪酸酰胺水解酶 (FAAH) 的作用快速代谢为花生四烯酸和极性代谢物，因此作用持续时间短得多。我们早期观察到，在大脑中大麻素本身水平大幅下降后，大麻素的作用仍然存在，这促使我们研究不可逆酰胺酶抑制剂苯甲基磺酰氟 (PMSF) 对大脑水平和大麻素药理作用的影响。如前所述，PMSF 预处理导致雄性小鼠抗伤害和低体温的 anandamide 剂量效应曲线左移。脑内和血浆中花生四烯酸、花生四烯酸和极性代谢物的水平在静脉注射后 1 分钟达到峰值。注射3 H-anandamide并在注射后5分钟保持高水平，此后水平急剧下降。在注射 1 或 10 mg/kg 3 H-anandamide 之前用 PMSF（30 mg/kg，i.p.）进行预处理，5 分钟后，与 3 H-anandamide 加媒介物注射获得的水平相比，anandamide 的脑水平提高。脑中花生四烯酸和极性代谢物的水平没有显着增加。 PMSF 预处理后脑内 anandamide 水平与药理活性之间存在明确的对应关系，表明该母体化合物是注射后 5 分钟发生的镇痛和体温降低的原因。这些结果进一步表明，代谢物对 anandamide 作用的贡献（如果有的话）将主要发生在以后的时间。
The endogenous cannabinoid anandamide produces cannabimimetic effects similar to those produced by Δ9-tetrahydrocannabinol (Δ9-THC), but has a much shorter duration of action due to its rapid metabolism to arachidonic acid and polar metabolites via action of fatty acid amide hydrolase (FAAH). Our earlier observations that anandamide's effects persisted after brain levels of anandamide itself had substantially dropped prompted us to examine the influence of the irreversible amidase inhibitor, phenylmethyl sulfonyl fluoride (PMSF), on the brain levels and pharmacological effects of anandamide. As shown previously, pretreatment with PMSF resulted in a leftward shift of the anandamide dose effect curves for antinociception and hypothermia in male mice. Brain and plasma levels of anandamide, arachidonic acid and polar metabolites peaked at 1 min after i.v. injection with3H-anandamide and remained high at 5 min post-injection, with levels falling sharply thereafter. Pretreatment with PMSF (30 mg/kg, i.p.) prior to an injection of 1 or 10 mg/kg3H-anandamide resulted 5 min later in enhanced brain levels of anandamide compared to those obtained with3H-anandamide plus vehicle injection. Levels of arachidonic acid and polar metabolites in brain were not significantly increased. The clear correspondence between brain levels of anandamide following pretreatment with PMSF and pharmacological activity suggests that this parent compound is responsible for the antinociception and hypothermia that occurred 5 min after injection. These results further suggest that metabolite contribution to anandamide's effects, if any, would occur primarily at later times.