kappa-agonist effects of the hallucinogen Salvinorin A

描述（由申请人提供）：鼠尾草素A是致幻植物鼠尾草（Salvia divinorum）的主要活性成分。含鼠尾草素A的产品最近已变得广泛可用（例如，最近的体外研究确定鼠尾草素A是一种选择性的、“超高”功效的κ-阿片受体激动剂。鼠尾草素A（一种非含氮二萜）是阿片受体的一种结构完全新颖的配体。迄今为止，关于鼠尾草素A在任何物种中的潜在体内κ-阿片样物质作用的已发表证据非常有限。被人类滥用的经典的多巴胺能致幻剂的作用被认为主要是由5 HT 2A受体的激动剂作用介导的;鼠尾草素A对5 HT 2A受体没有亲和力。目前尚不清楚鼠尾草素A的致幻/行为效应和经典的多巴胺能致幻剂的致幻/行为效应是否具有共同的下游底物。该提议的中心假设是鼠尾草素A在非人灵长类动物中具有中心穿透的“超高”功效κ激动剂的独特体内药理学特征。鼠尾草素A的作用将对通过多巴胺能5 HT 2A拮抗剂的预处理敏感，表明鼠尾草素A和经典多巴胺能致幻剂的共同下游作用。方法：该提案侧重于鼠尾草素A与合成κ-激动剂U69，593和选定的多巴胺能致幻剂的辨别、神经内分泌和行为效应的参数比较。具体而言，拟议的研究将确定这种机制上的新型致幻剂在新鼠尾草素A药物辨别中、在神经内分泌生物标志物测定（催乳素释放）中和在“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（κ-激动剂的显著作用）和其他行为作用的评级量表。鼠尾草素A诱导的作用的拮抗作用将用阿片受体拮抗剂（例如，纳美芬和GNTI）和选择性5 HT 2A拮抗剂。重要性：所提出的研究将确定鼠尾草素A的体内作用是否是由于对κ-阿片受体的“超高”功效激动剂作用，以及在灵长类动物中鼠尾草素A和经典的多巴胺能致幻剂的作用中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.