Kathuria Satish, Gaetani Silvana, Fegley Darren, Valiño Fernando, Duranti Andrea, Tontini Andrea, Mor Marco, Tarzia Giorgio, La Rana Giovanna, Calignano Antonio, Giustino Arcangela, Tattoli Maria, Palmery Maura, Cuomo Vincenzo, Piomelli Daniele
Department of Pharmacology, University of California, Irvine, California, USA.
Nat Med. 2003 Jan;9(1):76-81. doi: 10.1038/nm803. Epub 2002 Dec 2.
The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.
大麻的精神活性成分Δ⁹-四氢大麻酚在人体内产生由CB1大麻素受体介导的主观反应，这表明内源性大麻素可能有助于情绪控制。但Δ⁹-四氢大麻酚的多种效应使这些结果的解读变得模糊，并限制了直接大麻素激动剂的治疗潜力。另一种方法可能是开发通过阻止内源性大麻素失活来增强其作用的药物。在此，我们描述了一类强效、选择性且具有全身活性的脂肪酸酰胺水解酶抑制剂，该酶负责内源性大麻素花生四烯乙醇胺的降解。与临床使用的抗焦虑药物一样，在大鼠中，这些抑制剂在高架零迷宫试验中表现出类似苯二氮䓬的特性，并抑制隔离诱导的发声。这些效应伴随着花生四烯乙醇胺在大脑中的水平升高，并且可被CB1受体阻断所阻止。我们的结果表明，花生四烯乙醇胺参与情绪状态的调节，并指出抑制脂肪酸酰胺水解酶是一种创新的抗焦虑治疗方法。
