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kappa-agonist effects of the hallucinogen Salvinorin A

致幻剂 Salvinorin A 的 κ 激动剂作用

基本信息

批准号：
7388911
负责人：
EDUARDO R BUTELMAN
金额：
$ 19.63万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388911
关键词：
A 19 Affinity Agonist Behavioral Biological Assay Biological Factors Biological Markers Characteristics Clinical Complex Data Development Diterpenes Dose Effectiveness Hallucinogens Human In Vitro Internet Intoxication Knowledge Ligands Macaca mulatta Mediating Mediation NIH Program Announcements Narcotic Antagonists Neurobiology Neurosecretory Systems Observational Study Opioid Opioid Receptor Pharmaceutical Preparations Pharmacodynamics Phencyclidine Receptors Pituitary Hormones Plants Positron-Emission Tomography Prevention Primates Principal Investigator Prolactin Psychopharmacology Psychostimulant dependence Publishing Rate Relapse Reporting Rodent Salvia Sedation procedure Self Administration Serotonin Serum Site System Thinking Training analog base blind comparative drug discrimination follow-up in vivo innovation kappa opioid receptors nalmefene neuroimaging nonhuman primate novel prevent programs receptor research study salvinorin A sedative tool trend

项目摘要

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.

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。