Kappa-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse
Kappa-opioid receptor-mediated effects of the plant-derived hallucinogen, salvinorin A, on inverted screen performance in the mouse
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DOI：
10.1097/00008877-200512000-00005
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发表时间：
2005-12-01
影响因子：
1.6
通讯作者：
Woods, JH
中科院分区：
文献类型：
--
作者：
Fantegrossi, WE;Kugle, KM;Woods, JH
鼠尾草素A是一种天然存在于墨西哥薄荷Ska Maria Pastora（Salvia divinorum）中的抗氧化活性二萜，代表了第一种天然存在的κ-阿片受体激动剂。鼠尾草素A的化学结构在阿片类药物中是新颖的，因此定义了一种新的结构类别的κ-阿片受体选择性药物。很少有研究检查鼠尾草素A在体内的作用，并且更少的研究尝试使用选择性拮抗剂评估该化合物在μ-阿片样物质、δ-阿片样物质和κ-阿片样物质受体上的激动剂作用。在小鼠中，鼠尾草素A在倒置屏幕任务中破坏攀爬行为，表明镇静/运动不协调的快速但短暂的诱导。使用μ激动剂瑞芬太尼和合成κ激动剂U69，593观察到类似的效果。当行为等效剂量的所有三种阿片类药物与μ-阿片样物质，δ-阿片样物质，或κ-阿片样物质受体的选择性剂量的拮抗剂的挑战，结果表明，雷米芬太尼的运动效应介导的μ-受体，而鼠尾草素A和U69，593介导的κ-受体。尽管效力和有效性程度相似，但鼠尾草素A和U69，593对κ拮抗剂去甲-binaltorphamine的拮抗作用的敏感性不同。该后一发现与该化合物的新化学结构相结合，与最近的发现一致，即二萜鼠尾草素A可能以与更传统的κ-激动剂如苯乙酰胺U69，593在性质上不同的方式与κ-受体结合。这些κ-阿片类药物之间的这种药理学差异提高了开发其他基于二萜类药物的阿片类药物可能产生重要治疗化合物的可能性。
Salvinorin A is a pharmacologically active diterpene that occurs naturally in the Mexican mint Ska Maria Pastora (Salvia divinorum) and represents the first naturally occurring kappa-opioid receptor agonist. The chemical structure of salvinorin A is novel among the opioids, and thus defines a new structural class of kappa-opioid-receptor selective drugs. Few studies have examined the effects of salvinorin A in vivo, and fewer still have attempted to assess the agonist actions of this compound at mu-opioid, delta-opioid, and kappa-opioid receptors using selective antagonists. In the mouse, salvinorin A disrupted climbing behavior on an inverted screen task, indicating a rapid, but short-lived induction of sedation/motor incoordination. Similar effects were observed with the mu-agonist remifentanil and the synthetic kappa-agonist U69,593. When behaviorally equivalent doses of all three opioids were challenged with antagonists at doses selective for mu-opioid, delta-opioid, or kappa-opioid receptors, results suggested that the motoric effects of remifentanil were mediated by mu-receptors, whereas those of salvinorin A and U69,593 were mediated via kappa-receptors. Despite similar potencies and degrees of effectiveness, salvinorin A and U69,593 differed with regard to their susceptibility to antagonism by the kappa-antagonist nor-binaltorphamine. This later finding, coupled with the novel chemical structure of the compound, is consistent with recent findings that the diterpene salvinorin A may bind to the kappa-receptor in a manner that is qualitatively different from that of more traditional kappa-agonists such as the benzeneacetamide U69,593. Such pharmacological differences among these kappa-opioids raise the possibility that the development of other diterpene-based opioids may yield important therapeutic compounds.