MECHANISMS OF CANNABINOID'S ANTIEMETIC ACTIONS

描述（由申请人提供）：化疗诱导呕吐分为两个阶段，即立即和延迟。由化疗或放疗引起的呕吐的即时阶段可以用5-羟色胺5-HT 3受体拮抗剂治疗，然而，目前没有临床上可用的止吐药或止吐药联合治疗对所有患者的即时或延迟阶段有效。此外，尽管临床试验表明，地塞米松和/或物质P受体拮抗剂的添加改善了5-HT 3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，nabilone，是有效的止吐剂对化疗和放疗，和患者谁是保护在立即阶段也反应良好，在延迟阶段。最近的动物研究表明，不同结构和活性的异生物质大麻素（9-THC，CP 55，940和WIN 55，212-2）通过大麻素CB 1受体具有广谱止吐功效。实际上，β-THC及其类似物在不显著抑制小鼩（Cryptotis parva）的自发运动活动的剂量下防止顺铂诱导的呕吐的急性期。该提案的目标是定义大麻素对化疗和放疗产生的呕吐的即时和延迟阶段的广谱止吐性质，以及通过行为和生物化学手段揭示对外源性大麻素止吐能力的耐受性是否发展。具体目标是：1）异生物质大麻素的广谱止吐潜力的进一步表征和机制评估（9-THC，WIN 55，212-2，CP 55，940）对放射线、P物质和顺铂引起的迟发性呕吐的抑制作用; 2）显示是否联合施用β-THC可以增强已建立的止吐药（血清素5-HT 3-，多巴胺D2-和神经激肽NK 1-受体拮抗剂和地塞米松）对抗化疗和放疗诱导的呕吐; 3）通过行为研究确定对β-THC的止吐和运动抑制作用的耐受性的相对发展，放射性配体结合和G蛋白测定。这些结果将对这些“激动剂止吐药”的治疗效用具有重要意义。

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".