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）：Salvinorin A是致幻植物Salvia divinorum的主要活性成分。在美国，含萨尔维诺蛋白A的产品已广泛可用（例如，在互联网上），并有新兴的salvia divinorum用作致幻蛋白质的报道。 salvinorin A（非硝基二萜）是阿片受体的结构上完全新颖的配体。迄今为止，有非常有限的公开证据证明了萨尔维诺蛋白A在任何物种中的体内kappa-阿片类药物的潜在作用。人们认为，被人类滥用的经典血清素能致幻剂的作用主要是由5HT2A受体的激动剂作用介导的。 Salvinorin A在5HT2A受体下没有亲和力。尚不清楚Salvinorin A和经典血清素能致幻剂的致幻 /行为作用是否具有共同的下游底物。该提案的中心假设是萨尔维诺蛋白A具有非人类灵长类动物中的集中渗透，“超高”功效的“超高”功效Kappa激动剂的独特体内药理学特征。 Salvinorin A的作用将对血清素能5HT2A拮抗剂进行预处理敏感，表明salvinorin A和经典的血清素能致幻剂的常见下游效应。方法：该提案重点介绍了salvinorin a对合成Kappa激动剂的歧视性，神经内分泌和行为作用的参数比较，U69,593以及选定的5-羟色胺能致幻剂。具体而言，提出的研究将确定这种机械性新颖的幻觉症的效能，有效性（明显的功效），受体的选择性和作用持续时间在新的salvinorin a药物歧视中，在神经内分泌生物标志物测定（催乳素释放）中，在“盲目释放”中使用“盲目的研究”，使用评分量表来镇定效应（一种较高的行为效应）。 Salvinorin A诱导作用的拮抗作用将以阿片类受体拮抗剂（例如Nalmefene和Gnti）和选择性的5HT2A拮抗剂的形式系统地表征。意义：拟议的研究将确定萨尔维诺蛋白A的体内作用是否是由于“超高”功效激动剂在Kappa-阿片受体上的作用，以及是否存在相互作用的药理学底物对Salvinorin a和经典的血清素疗法幻觉剂的作用相互作用。