MECHANISMS OF CANNABINOIDS ANTIEMETIC ACTIONS

恶心和呕吐是与癌症化疗相关的常见副作用，严重影响患者的生活质量，并可能导致拒绝进一步的化疗。几类药物(多巴胺D2受体拮抗剂、5-羟色胺5-羟色胺受体拮抗剂和大麻素激动剂)在预防化疗引起的呕吐方面似乎是有用的。与D2和5-HT3受体拮抗剂不同，临床上可用的大麻素的止吐作用机制目前尚不清楚。然而，基础和临床研究清楚地表明，三角洲-9-四氢大麻酚(Delta9-THC)及其合成类似物纳比隆具有显著的止吐效果。大麻素CB1和CB2受体选择性拮抗剂的最新进展，以及一种通用的、廉价的新的呕吐动物模型的引入和药理学特征，为研究大麻素受体对其止吐作用的机制提供了机会。化疗药物顺铂在动物和人类身上都是最强的感情剂。顺铂给药也会以剂量和时间依赖的方式在最小的地鼠身上产生呕吐。此外，Delta9-THC和5-HT3受体拮抗剂都可以防止顺铂引起的呕吐。另一方面，5-HT3和D2受体激动剂在最小的地鼠身上也能有效而快速地诱导呕吐。用Delta9-THC或D2受体拮抗剂预防阿朴吗啡(一种多巴胺D2激动剂)引起的呕吐。本研究的具体目的是：1)探讨Delta9-THC在阻断化疗药物顺铂引起呕吐的止吐作用中起作用的是哪种大麻受体(S)；b)用放射配基结合技术确定所涉及的止吐大麻受体(S)的存在；c)了解Delta9-THC的止吐活性是否与其他类别的大麻激动剂(甲烷胺，CP，55,940和Win 55,212-2)的代表相同。具体目的2)建立Delta9-THC及其相关衍生物在最小地鼠体内的药理图谱，以确定其他行为效应是否有助于大麻类化合物的止吐特性。具体目的3)由于Delta9-THC有效地阻断了阿朴吗啡(一种D2激动剂)在猫和最小的地鼠身上诱导呕吐的能力，因此将对负责这种作用的大麻素受体进行鉴定。Delta9-THC抑制5-HT3激动剂2-甲基5-羟色胺引起的呕吐的能力也将被研究。这一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.