MECHANISMS OF CANNABINOIDS ANTIEMETIC ACTIONS

恶心和呕吐是癌症化疗的常见副作用，严重影响患者的生活质量，并可能导致拒绝进一步化疗。 几类药物（多巴胺D2受体拮抗剂、5-羟色胺5-HT 3受体拮抗剂和大麻素激动剂）似乎可用于预防化疗诱导的呕吐。 与D2-和5-HT 3-受体拮抗剂不同，临床上有用的大麻素的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）及其合成类似物大麻隆（nabilone）表现出显著的止吐功效。 大麻素CB 1和CB 2受体的选择性拮抗剂的最新发展，以及一种通用的，廉价的，新的动物模型呕吐的介绍和药理学表征[最小的鼩（Cryptotis parva）];提供了机会，调查大麻素受体机制负责其止吐作用。 化疗药物顺铂是动物和人类最有效的致情物质，顺铂给药也以剂量和时间依赖的方式在最小的鼩 鼱中产生呕吐。 此外，delta 9-THC和5-HT 3受体拮抗剂都能防止顺铂诱导的呕吐。 另一方面，5-HT 3-和D2-受体激动剂，有效和迅速地诱导最小的鼩 鼱呕吐。 用delta 9-THC或D2-受体拮抗剂预处理可防止阿扑吗啡（一种多巴胺D2激动剂）在最小的鼩 鼱中产生的呕吐。本研究的具体目标是：具体目的1）a）研究哪种大麻素受体负责δ 9-THC在阻断化疗剂顺铂产生呕吐的能力中的止吐作用; B）通过放射性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δ 9-THC的止吐活性是否被其他种类的大麻素激动剂的公知代表物（methanandamide，CP，55，940和WIN 55，212-2）共享。 具体目的2）建立delta 9-THC和相关衍生物在最小鼩中的药理学特征，以确定其他行为效应是否有助于大麻素的止吐特性。 具体目的3）由于δ 9-THC有效地阻断阿扑吗啡（一种D2激动剂）诱导猫和最小鼩的呕吐的能力，因此将表征负责该作用的大麻素受体。 还将研究δ 9-THC抑制由5-HT 3激动剂2-甲基5-HT产生的呕吐的能力。 研究结果将确定大麻素受体在呕吐回路中的重要作用，并可能涉及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.