MECHANISMS OF CANNABINOID'S ANTIEMETIC ACTIONS

大麻素的止吐作用机制

• 批准号: 7031766
• 负责人: NISSAR A DARMANI
• 金额: $ 15.56万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7031766
• 关键词: Mammalia; anandamide; antiemetics; cannabinoid receptor; cannabinoids; chemosensitizing agent; cis platinum compound; dexamethasone; dopamine agonists; dopamine receptor; drug adverse effect; drug interactions; drug screening /evaluation; drug tolerance; emesis; gastrointestinal disorder chemotherapy; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pharmacokinetics; serotonin inhibitor; serotonin receptor; therapy adverse effect

DESCRIPTION (provided by applicant): Chemotherapy induces emesis in two phases, immediate and delayed. The immediate phase of vomiting induced by chemo- or radiotherapy can be treated with serotonin 5-HT3 receptor antagonists, however, there is currently no clinically available antiemetic or antiemetic combination therapy that is effective in all patients either for the immediate or the delayed phase. Moreover, although clinical trials indicate that addition of dexamethasone and/or substance P receptor antagonists improve the antiemetic activity of 5-HT3 antagonists in both acute and delayed emesis, these agents are not effective in all patients. (9- Tetrahydrocannabinol ((9-THC) and its synthetic analog, nabilone, are effective antiemetics against chemo- and radiotherapy, and patients who are protected during the immediate phase also respond well during the delayed phase. Recent animal studies have shown that xenobiotic cannabinoids of diverse structure and activity ((9-THC, CP 55, 940 and WIN 55, 212-2) have broadspectrum antiemetic efficacy via cannabinoid CB1 receptors. Indeed, (9-THC and its analogs prevent the acute phase of cisplatin-induced emesis at doses which do not significantly suppress spontaneous motor activity in the least shrew (Cryptotis parva). The goals of this proposal are to define the broadspectrum antiemetic nature of cannabinoids against both the immediate and delayed phases of emesis produced by chemo and radiotherapy as well as revealing by behavioral and biochemical means whether tolerance develop to the antiemetic capacity of xenobiotic cannabinoids. The specific aims are: 1) Further characterization and mechanistic evaluation of broadspectrum antiemetic potential of xenobiotic cannabinoids ((9-THC, WIN 55, 212-2, CP 55, 940) in the least shrew against diverse emetic stimuli such as radiation, substance P and cisplatin-induced delayed emesis; 2) To show whether co-administration of (9-THC can potentiate the antivomiting efficacy of established antiemetics (serotonin 5-HT3-, dopamine D2- and neurokinin NK1-receptor antagonists and dexamethasone) against chemo- and radiotherapy-induced vomiting; 3) Determination of relative development of tolerance to antiemetic and motor suppressive effects of (9-THC by means of behavioral studies, radioligand binding and G-protein assays. The results will have important implications for the therapeutic utility of these "agonist antiemetics".

描述(申请人提供)：化疗导致呕吐分两个阶段，立即和延迟。化疗或放疗引起的即刻呕吐可以用5-羟色胺5-HT3受体拮抗剂治疗，但目前还没有临床可用的止吐或止吐联合疗法，对所有患者的即刻或延迟期都有效。此外，尽管临床试验表明，地塞米松和/或P物质受体拮抗剂的加入改善了5-HT3拮抗剂在急性和迟发性呕吐中的止吐活性，但这些药物并不是对所有患者都有效。(9-四氢大麻酚(9-THC)及其合成类似物纳比隆是对抗化疗和放射治疗的有效止吐药物，在立即阶段得到保护的患者在延迟阶段也反应良好。最近的动物研究表明，不同结构和活性的异种大麻素(9-THC，CP 55,940和Win 55,212-2)通过大麻素CB1受体具有广谱止吐作用。事实上，(9-THC及其类似物)可以预防顺铂引起的呕吐的急性期，剂量对最小的地鼠(隐鼠)的自发运动活动没有明显的抑制作用。这项提案的目的是确定大麻类化合物对化疗和放射治疗引起的即时和延迟性呕吐的广谱止吐性质，并通过行为和生化手段揭示耐受性是否发展到异种大麻素的止吐能力。其具体目的是：1)进一步表征和评估异种大麻素(9-THC，Win 55,212-2，CP 55,940)对辐射、P物质和顺铂诱导的延迟性呕吐等多种呕吐刺激的广谱止吐作用；2)证明联合应用(9-THC)是否能增强已有的抗呕吐药物(5-羟色胺5-HT3、多巴胺D2和神经激肽NK1受体拮抗剂和地塞米松)对化疗和放射诱导的呕吐的止吐效果；3)通过行为学、放射配基结合和G蛋白测定，确定9-THC对止吐和运动抑制作用耐受性的相对发展。这一结果将对这些“激动剂止吐剂”的治疗效果具有重要意义。