Butelman Eduardo R, Prisinzano Thomas E, Deng Haiteng, Rus Szymon, Kreek Mary Jeanne
Laboratory on the Biology of Addictive Diseases, Rockefeller University (Box 171), 1230 York Ave., New York, NY 1006, USA.
J Pharmacol Exp Ther. 2009 Feb;328(2):588-97. doi: 10.1124/jpet.108.145342. Epub 2008 Nov 10.
Salvinorin A is the main active component of the widely available hallucinogenic plant, Salvia divinorum. Salvinorin A is a selective high-efficacy kappa-agonist in vitro, with some unique pharmacodynamic properties. Descriptive reports show that salvinorin A-containing products produce robust behavioral effects in humans. However, these effects have not been systematically characterized in human or nonhuman primates to date. Therefore, the present studies focused on the characterization of overt effects of salvinorin A, such as sedation (operationally defined as unresponsiveness to environmental stimuli) and postural relaxation, previously observed with centrally penetrating kappa-agonists in nonhuman primates. Salvinorin A was active in these endpoints (dose range, 0.01-0.1 mg/kg i.v.) in nonhuman primates (n = 3-5), similar to the synthetic kappa-agonist U69,593 [(+)-(5alpha,7alpha,8beta)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]-dec-8-yl]-benzeneacetamide], used for comparison herein. Salvinorin A effects could be prevented by a clinically available opioid antagonist, nalmefene (0.1 mg/kg), at doses known to block kappa-receptor-mediated effects in nonhuman primates. When injected intravenously, salvinorin A (0.032 mg/kg) could enter the central nervous system (as reflected in cisternal cerebrospinal fluid) within 1 min and reach concentrations that are in the reported range of the affinity (K(i)) of this ligand for brain kappa-receptors. Consistent with this finding, specific translationally viable behavioral effects (e.g., facial relaxation and ptosis) could also be detected within 1 to 2 min of injection of salvinorin A. These are the first studies documenting rapid unconditioned effects of salvinorin A in a primate species, consistent with descriptive reports of rapid and robust effects of this powerful hallucinogen in humans.
Salvinorin A是广泛可得的致幻植物鼠尾草（Salvia divinorum）的主要活性成分。Salvinorin A在体外是一种选择性高效κ-激动剂，具有一些独特的药效学特性。描述性报告显示，含Salvinorin A的产品在人类身上会产生显著的行为效应。然而，迄今为止，这些效应尚未在人类或非人类灵长类动物中得到系统的表征。因此，本研究聚焦于Salvinorin A明显效应的表征，如镇静（操作定义为对环境刺激无反应）和姿势放松，此前在非人类灵长类动物中使用中枢穿透性κ-激动剂时曾观察到这些效应。Salvinorin A在非人类灵长类动物（n = 3 - 5）的这些终点指标上具有活性（剂量范围为0.01 - 0.1 mg/kg静脉注射），类似于用于本研究比较的合成κ-激动剂U69,593 [（+）-（5α，7α，8β）-N-甲基-N-[7-（1-吡咯烷基）-1-氧杂螺[4.5]癸-8-基]-苯乙酰胺]。Salvinorin A的效应可被临床可用的阿片类拮抗剂纳美芬（0.1 mg/kg）阻断，该剂量已知可在非人类灵长类动物中阻断κ-受体介导的效应。静脉注射时，Salvinorin A（0.032 mg/kg）可在1分钟内进入中枢神经系统（如脑池脑脊液所示），并达到该配体对脑κ-受体亲和力（K(i)）报告范围内的浓度。与此发现一致，在注射Salvinorin A后1至2分钟内也可检测到特定的具有转化可行性的行为效应（如面部放松和上睑下垂）。这些是首次记录Salvinorin A在灵长类动物物种中快速无条件效应的研究，与关于这种强效致幻剂在人类中快速且显著效应的描述性报告一致。
