Receptor mechanism and antiemetic activity of structurally-diverse cannabinoids against radiation-induced emesis in the least shrew
Receptor mechanism and antiemetic activity of structurally-diverse cannabinoids against radiation-induced emesis in the least shrew
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DOI：
10.1016/j.ejphar.2007.01.093
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发表时间：
2007-06-01
影响因子：
5
通讯作者：
Ramirez, Juan
中科院分区：
文献类型：
--
作者：
Darmani, Nissar A.;Janoyan, Jano J.;Ramirez, Juan
异生大麻素 CB1/CB2 受体激动剂似乎具有广谱止吐活性，因为它们通过刺激 CB1 受体来防止多种催吐刺激物（包括化疗药物顺铂、血清素 5-HT3 受体激动剂、多巴胺 D-2/D-3 受体激动剂和吗啡）引起的呕吐。本研究的目的是评估结构多样化的大麻素 [Delta(9)-THC，（delta-9-四氢大麻酚）； (δ(8)-THC、δ-8-四氢大麻酚)； WIN55，212-2，(R(+)-[2,3-二氢-5-甲基-3-(吗啉基))，甲基]吡咯醇[1,2,3-de]-1,4苯并恶嗪基]-(1-萘基)亚甲酮甲磺酸酯)； CP55,940，((-)-3-[2-羟基-4-(1,1-二甲基庚基]-4-[3-羟丙基]环己烷-1-醇))，可以预防辐射引起的呕吐。暴露于全身辐射（0、5、7.5 和 10 Gy）会导致最小鼩鼱（Cryptotis parva）以剂量依赖性方式剧烈呕吐（ED50 = 5.99 (5.77-6.23) Gy），并且所有动物在最高测试辐射剂量下都会呕吐。此外，在治疗后一小时内，辐射暴露以非剂量依赖性方式显着但轻微地降低了运动行为。 CB1/CB2 受体激动剂以剂量依赖性方式阻断辐射诱发的呕吐 (10 Gy)，其 ID50 效力顺序如下：CP55,940 (0.11 (0.09-0.12) mg/kg)> WIN55,212,2 (3.65 (3.15-4.23) mg/kg) = Delta(8)-THC (4.36(3.05-6.22)mg/kg)>Delta(9)-THC(6.76(5.22-8.75)mg/kg)。尽管 Delta(8)-THC 相对于其异构体 Delta(9)-THC 具有更大的止吐效力和功效，但这种情况并不常见，因为后者大麻素在功能测定中对大麻素受体具有更高的亲和力和效力，但目前的数据支持一项儿童临床研究的结果，表明 A8-THC 可以完全防止呕吐。尚未在接受化疗或放疗的癌症患者中临床观察到 Delta(9)-THC 的这种效应。大麻素通过刺激大麻素 CB1 受体来防止诱发呕吐，因为 CB1 (SR141716A) - 而不是 CB2 (SR144528) - 受体拮抗剂逆转了观察到的呕吐频率减少和 Delta(9)-THC 或 CP55,940 针对辐射诱发呕吐提供的鼩鼱呕吐保护。这些发现进一步表明，最小的鼩鼱可以用作一种多功能且廉价的小动物模型，以快速筛选研究性止吐药预防辐射诱发呕吐的功效。 (c) 2007 Elsevier B.V. 保留所有权利。
Xenobiotic cannabinoid CB1/CB2-receptor agonists appear to possess broad-spectrum antiemetic activity since they prevent vomiting produced by a variety of emetic stimuli including the chemotherapeutic agent cisplatin, serotonin 5-HT3-receptor agonists, dopamine D-2/D-3-receptor agonists and morphine, via the stimulation of CB1-receptors. The purpose of this study was to evaluate whether structurally-diverse cannabinoids [Delta(9)-THC, (delta-9-tetrahydrocannabinol); (Delta(8)-THC, delta-8-tetrahydrocannabinol); WIN55,212-2, (R (+)-[2,3-dihydro-5-methyl-3-(morpholinyl)), methyl] pyrolol [1,2,3-de]-1,4 benzoxazinyl]-(1-naphthalenyl) methenone mesylate); and CP55,940, ((-)-3-[2-hydroxy-4-(1,1-dimethylheptyl]-4-[3-hydroxypropyl] cyclohexane-1-ol)), can prevent radiation-induced emesis. Exposure to total body radiation (0, 5, 7.5 and 10 Gy) caused robust emesis in the least shrew (Cryptotis parva) in a dose-dependent manner (ED50 = 5.99 (5.77-6.23) Gy) and all animals vomited at the highest tested dose of radiation. In addition, the radiation exposure reduced locomotor behaviors to a significant but mild degree in a non-dose-dependent fashion up to one hour post-treatment. Radiation-induced emesis (10 Gy) was blocked in a dose-dependent manner by the CB1/CB2-receptor agonists with the following ID50 potency order: CP55,940 (0.11 (0.09-0.12) mg/kg)> WIN55,212,2 (3.65 (3.15-4.23) mg/kg) = Delta(8)-THC (4.36 (3.05-6.22) mg/kg)>Delta(9)-THC(6.76 (5.22-8.75)mg/kg). Although the greater antiemetic potency and efficacy of Delta(8)-THC relative to its isomer Delta(9)-THC is unusual as the latter cannabinoid possesses higher affinity and potency for cannabinoid receptors in functional assays, the current data support the results of a clinical study in children suggestive of complete protection from emesis by A8-THC. This effect has not been clinically observed for Delta(9)-THC in cancer patients receiving chemo- or radiation-therapy. Cannabinoids prevented the induced emesis via the stimulation of cannabinoid CB1-receptors because the CB1 (SR141716A) - and not the CB2 (SR144528) - receptor antagonist reversed both the observed reduction in emesis frequency and shrew emesis protection afforded by either Delta(9)-THC or CP55,940 against radiation-induced emesis. These findings further suggest that the least shrew can be utilized as a versatile and inexpensive small animal model to rapidly screen the efficacy of investigational antiemetics for the prevention of radiation-induced emesis. (c) 2007 Elsevier B.V. All rights reserved.