MECHANISMS OF CANNABINOID'S ANTIEMETIC ACTIONS

描述（由申请人提供）：化疗引起的呕吐分即时和延迟两期。化疗或放疗引起的即时呕吐可以用5-羟色胺5-HT3受体拮抗剂治疗，然而，目前临床上还没有一种止吐或止吐联合治疗对所有患者的即时或延迟期都有效。此外，尽管临床试验表明，添加地塞米松和/或P物质受体拮抗剂可改善5-HT3拮抗剂在急性和延迟性呕吐中的止吐活性，但这些药物并非对所有患者都有效。(9-四氢大麻酚（9- thc）及其合成类似物纳比龙是有效的抗化疗和放疗止吐剂，在即时期受到保护的患者在延迟期也有良好的反应。最近的动物研究表明，不同结构和活性的外源大麻素(（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，9-四氢大麻酚及其类似物在不显著抑制最小鼩鼱自发运动活动的剂量下防止顺铂诱导的急性期呕吐。本提案的目标是确定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，以及通过行为和生化手段揭示是否对异种大麻素的止吐能力产生耐受性。具体目的是：1)进一步表征和机制评价外源大麻素(（9-THC, WIN 55,212 -2, CP 55,940）在最小鼠体内抗多种呕吐刺激（如辐射、P物质和顺铂诱导的延迟呕吐）的广谱止吐潜力；2)观察联合使用（9-四氢大麻酚）是否能增强已建立的止吐药（血清素5-HT3-、多巴胺D2-和神经动素nk1受体拮抗剂和地塞米松）对化疗和放疗引起的呕吐的止吐效果；3)通过行为学研究、放射配体结合和g蛋白测定测定（9-四氢大麻酚）止吐和运动抑制作用耐受的相对发展。该结果将对这些“激动剂止吐剂”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".