MECHANISMS OF CANNABINOIDS ANTIEMETIC ACTIONS

恶心和呕吐是癌症化疗常见的副作用，严重影响患者的生活质量，并可能导致患者拒绝进一步化疗。几类药物（多巴胺D2受体拮抗剂，5-羟色胺5-HT3受体拮抗剂和大麻素激动剂）似乎对预防化疗诱导的呕吐有用。与D2-和5-HT3受体拮抗剂不同，临床上有用的大麻素止吐作用的机制目前尚不清楚。然而，基础和临床研究清楚地表明，δ -9-四氢大麻酚（δ -9- thc）及其合成类似物纳比龙具有显著的止吐功效。大麻素CB1和CB2受体选择性拮抗剂的最新进展，以及一种多功能、廉价的新型呕吐动物模型[最小鼩鼱（隐鼩）]的引入和药理学表征；提供机会来调查大麻素受体机制负责他们的止吐作用。化疗药物顺铂是动物和人类中最有效的情绪源物质。顺铂给药也以剂量和时间依赖的方式在最小的鼠中产生呕吐。此外，δ 9- thc和5-HT3受体拮抗剂均可预防顺铂诱导的呕吐。另一方面，5-HT3-和d2受体激动剂在最小的鼩鼱中有效且迅速地诱导呕吐。用δ 9-四氢大麻酚或D2受体拮抗剂预处理可以防止阿波啡（一种多巴胺D2激动剂）引起的呕吐。本研究的具体目标是：具体目的1)a)研究哪种大麻素受体在阻断化疗药物顺铂产生呕吐的能力中负责delta - 9- thc的止吐作用；B)通过放射配体结合技术确定所涉及的止吐大麻素受体的存在；c)发现delta9-THC的止吐活性是否与其他类大麻素激动剂（甲胺，CP, 55,940和WIN 55,212 -2）的知名代表相同。2)建立δ 9-四氢大麻酚及其衍生物在最小鼩鼱中的药理学特征，以确定大麻素的止吐特性是否与其他行为作用有关。3)由于δ 9- thc能有效阻断阿帕吗啡（一种D2激动剂）在猫和鼩鼱中诱导呕吐的能力，大麻素受体负责这种作用将被表征。delta9-THC抑制5-HT3激动剂2-甲基5-HT产生的呕吐的能力也将被研究。该结果将确定大麻素受体在呕吐回路中的重要作用，并可能暗示内源性大麻素的止吐作用。

Nausea and vomiting are the common side effects associated with cancer chemotherapy that profoundly affects the patients' quality of life and may lead to refusal of further chemotherapy treatment. Several classes of drugs (dopamine D2 receptor antagonists, serotonin 5-HT3 receptor antagonists and cannabinoid agonists) appear to be useful in the prevention of chemotherapeutically-induced emesis. Unlike D2- and 5-HT3- receptor antagonists, the mechanism of the antiemetic action of clinically useful cannabinoids is presently unknown. However, basic and clinical studies clearly show that delta-9- tetrahydrocannabinol (delta9-THC) and its synthetic analog nabilone, demonstrate significant antiemetic efficacy. The recent developments of selective antagonists for cannabinoid CB1 and CB2 receptors, as well as the introduction, and pharmacological characterization of a versatile, inexpensive, new animal model of emesis [the least shrew (Cryptotis parva)]; provide the opportunity to investigate the cannabinoid receptor mechanisms responsible for their antiemetic actions. The chemotherapeutic agent cisplatin is the most potent emotogenic substance both in animals and man. Cisplatin administration also produces emesis in the least shrew in a dose- and time-dependent manner. Moreover, both delta9-THC and 5-HT3 receptor antagonists prevent the cisplatin-induced vomiting in this species. On the other hand, 5-HT3- and D2-receptor agonists, potently and rapidly induce vomiting in the least shrew. Pretreatment with either delta9-THC or D2-receptor antagonists prevent the emesis produced by apomorphine (a dopamine D2 agonist) in the least shrew). The specific goals of this investigation are: Specific aim 1) a) To investigate which cannabinoid receptor(s) is responsible for the antiemetic action of delta9-THC in blocking the ability of the chemotherapeutic agent, cisplatin, to produce emesis; b) to determine the presence of the implicated antiemetic cannabinoid receptor(s) by radioligand binding techniques; c) to find whether delta9-THC's antiemetic activity is shared by the well known representatives of other classes of cannabinoid agonists (methanandamide, CP, 55, 940 and WIN 55, 212-2). Specific aim 2) To establish the pharmacological profile of delta9-THC and related derivatives in the least shrew in order to determine whether other behavioral effects contribute to the antiemetic properties fo cannabinoids. Specific aim 3) Since delta9-THC potently blocks the ability of apomorphine (a D2 agonist) to induce emesis in the cat and the least shrew, the cannabinoid receptors responsible for this effect will be characterized. The ability of delta9-THC to inhibit emesis produced by the 5-HT3, agonist, 2-methyl 5-HT, will be also investigated. The results will define an important role for the cannabinoid receptors in the vomiting circuits and may implicate an antiemetic role for the endogenous cannabinoids.