kappa-agonist effects of the hallucinogen Salvinorin A

描述（由申请人提供）：Salvinorin A是致幻植物鼠尾草（Salvia divinorum）的主要活性成分。含有Salvinorin a的产品最近变得广泛可用（例如，在互联网上），并且有新出现的报道称，丹参在美国被用作致幻剂。最近的体外研究发现Salvinorin a是一种选择性的，“超高”功效的kappa-阿片受体激动剂。Salvinorin A（一种非氮二萜）是一种结构上完全新颖的阿片受体配体。迄今为止，关于salvinorin A在任何物种中潜在的体内kappa-opioid效应的已发表证据非常有限。被人类滥用的经典5 -羟色胺能致幻剂的作用被认为主要是通过5HT2A受体的激动剂作用介导的；salvinorin A对5HT2A受体没有亲和力。目前尚不清楚salvinorin A的致幻/行为效应是否与经典的5 -羟色胺致幻剂具有共同的下游底物。该提案的中心假设是salvinorin A在非人类灵长类动物中具有独特的中心穿透性，“超高”功效的kappa激动剂的体内药理学特征。Salvinorin A的作用将对5 -羟色胺能5HT2A拮抗剂的预处理敏感，这表明Salvinorin A和经典的5 -羟色胺能致幻剂具有共同的下游作用。方法：本研究将salvinorin a与合成的kappa激动剂U69,593和选定的5 -羟色胺能致幻剂的鉴别、神经内分泌和行为效应进行参数比较。具体来说，拟议的研究将确定这种机制新颖的致幻剂在新的salvinorin a药物鉴别、神经内分泌生物标志物测定（催乳素释放）和“盲”观察性研究中的效力、有效性（表观功效）、受体选择性和作用持续时间，使用镇静（kappa激动剂的突出作用）和其他行为效应的评分量表。salvinorin a诱导的拮抗作用将通过阿片受体拮抗剂（如纳美芬和GNTI）和选择性5HT2A拮抗剂系统地表征。意义：拟开展的研究将确定salvinorin A的体内作用是否源于kappa-阿片受体的“超高”效激动剂作用，以及salvinorin A与经典5 -羟色胺能致幻剂在灵长类动物中的作用是否存在相互作用的药理学底物。

DESCRIPTION (provided by applicant): Salvinorin A is the main active component of the hallucinogenic plant, Salvia divinorum. Salvinorin A-containing products have recently become widely available (e.g., on the internet), and there are emerging reports of Salvia divinorum use as a hallucinogen, in the U.S. Very recent in vitro studies identified salvinorin A as a selective, "ultra-high" efficacy kappa-opioid receptor agonist. Salvinorin A (a non-nitrogenous diterpene) is a structurally completely novel ligand for opioid receptors. To date, there is very limited published evidence on the potential in vivo kappa-opioid effects of salvinorin A, in any species. The effects of classic serotonergic hallucinogens abused by humans are thought to be primarily mediated by agonist actions at 5HT2A receptors; salvinorin A does not have affinity at 5HT2A receptors. It is unknown whether the hallucinogenic / behavioral effects of salvinorin A and those of classic serotonergic hallucinogens share common downstream substrates. The Central Hypothesis of this proposal is that salvinorin A has the unique in vivo pharmacological profile of a centrally-penetrating, "ultra-high" efficacy kappa-agonist in nonhuman primates. Salvinorin A's effects will be sensitive to pretreatment by a serotonergic 5HT2A antagonist, indicating common downstream effects of salvinorin A and classic serotonergic hallucinogens. Approach: This proposal focuses on a parametric comparison of the discriminative, neuroendocrine and behavioral effects of salvinorin A to those of the synthetic kappa-agonist, U69,593, and to selected serotonergic hallucinogens. Specifically, the proposed studies would determine the potency, effectiveness (apparent efficacy), receptor selectivity and duration of action of this mechanistically novel hallucinogen in a new salvinorin A drug discrimination, in a neuroendocrine biomarker assay (prolactin release) and in "blind" observational studies, using rating scales for sedation (a prominent effect of kappa-agonists) and other behavioral effects. Antagonism of salvinorin A-induced effects will be systematically characterized with opioid receptor antagonists (e.g., nalmefene and GNTI), and with a selective 5HT2A antagonist. Significance: The proposed studies would determine whether the in vivo effects of salvinorin A are due to "ultra-high" efficacy agonist effects at kappa-opioid receptors, and whether there are interacting pharmacological substrates in the effects of salvinorin A and classic serotonergic hallucinogens, in primates.