Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva)
Delta-9-tetrahydrocannabinol differentially suppresses emesis versus enhanced locomotor activity produced by chemically diverse dopamine D2/D3 receptor agonists in the least shrew (Cryptotis parva)
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DOI：
10.1016/j.pbb.2004.10.019
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Crim, JL
中科院分区：
文献类型：
--
作者：
Darmani, NA;Crim, JL
大麻的主要精神活性成分，δ-9-四氢大麻酚（δ（9）-THC），抑制癌症患者由顺铂等化疗药物引起的恶心和呕吐。顺铂通过包括多巴胺在内的多种催吐刺激诱导呕吐。目前，关于Δ（9）-THC是否可以防止由多巴胺能激动剂如阿扑吗啡产生的呕吐存在争议。本研究利用最小的鼩 鼱来评估止吐潜力和大麻素受体，Delta（9）-THC可以通过该大麻素受体防止由对D-2和D-3受体具有不同选择性的四种多巴胺受体激动剂产生的呕吐，即，一种非选择性多巴胺受体激动剂（阿扑吗啡）、一种D-2-优选受体激动剂（喹吡罗）和两种D-3-优选受体激动剂（喹咯烷和7-OH DPAT）。此外，相对于其止吐剂量，还评价了Delta（9）-THC在多巴胺D-2/D-3受体激动剂处理的鼩中的运动抑制剂量。因此，向不同组的鼠注射载体（V）或不同剂量的Delta（9）-THC [0.5、1、2.5、5或10 mg/kg，腹膜内（i. p.）]。在施用2 mg/kg剂量的四种引用的D-2/D-3激动剂之一之前10分钟。在最后一次注射后，立即记录每只大鼠接下来30分钟的呕吐频率。为了研究哪种大麻素受体参与Delta（9）-THC的止吐作用，不同剂量的CB 1受体拮抗剂SR 141716 A [0、5、10和20 mg/kg，皮下（s.c.）]在注射完全有效的止吐剂量的Delta（9）-THC（5 mg/kg，腹膜内）之前10分钟，对鼠给药。10分钟后，给每只处理过的鼩 鼱施用2 mg/kg剂量的阿扑吗啡。记录下30分钟内的呕吐频率。对于运动研究，在注射载体或2 mg/kg剂量的四种D2/D3受体激动剂之一之前10分钟，不同组的大鼠接受载体或不同剂量的Delta（9）-THC（0、5、10、20或30 mg/kg）。在接下来的30分钟内，通过计算机视频跟踪系统记录运动行为三联体（自发运动活动、运动总持续时间和直立频率）。δ（9）-THC剂量依赖性地减弱呕吐频率，并完全保护鼩 鼱免于由四种所引用的多巴胺D2/D3受体激动剂中的每一种产生的呕吐，其ID 50范围为1至4 mg/kg。SR 141716 A可逆转Delta（9）-THC对阿扑吗啡诱导的呕吐的止吐活性。δ（9）-THC也不同程度地抑制多巴胺D2/D3受体激动剂处理的鼩的三联运动活动，ID 50范围为7至21 mg/kg。结果表明，在D-2/D-3受体激动剂处理的大鼠中，Delta（9）-THC通过大麻素CB 1受体以有效和剂量依赖性的方式防止呕吐，剂量远低于引起显著运动抑制的剂量。(C)2004年爱思唯尔公司All rights reserved.
The principal psychoactive component of marijuana, delta-9-tetrahydrocannabinol (Delta(9)-THC), suppresses nausea and vomiting in cancer patients caused by chemotherapeutics such as cisplatin. Cisplatin induces vomiting via a number of emetic stimuli, including dopamine. Currently, there is controversy as to whether Delta(9)-THC can prevent emesis produced by dopaminergic agonists such as apomorphine. The present investigation utilizes the least shrew to evaluate the antiemetic potential and the cannabinoid receptor by which Delta(9)-THC may prevent emesis produced by four dopamine receptor agonists with differing selectivity for D-2 and D-3 receptors, i.e., a nonselective dopamine receptor agonist (apomorphine), a D-2-preferring receptor agonist (quinpirole), and two D-3-preferring receptor agonists (quinelorane and 7-OH DPAT). In addition, relative to its antiemetic doses, the motor suppressive doses of Delta(9)-THC in dopamine D-2/D-3-receptor-agonist-treated shrews were also evaluated. Thus, different groups of shrews were injected with either vehicle (V) or varying doses of Delta(9)-THC [0.5, 1, 2.5, 5, or 10 mg/kg, intraperitoneat (i.p.)] 10 min prior to administration of a 2 mg/kg dose of one of the four cited D-2/D-3 agonists. Immediately after the last injection, the frequency of vomiting for each shrew was recorded for the next 30 min. To investigate which cannabinoid receptor is involved in the antiemetic action of Delta(9)-THC, various doses of the CB1 receptor antagonist SR 141716A [0, 5, 10, and 20 mg/kg, subcutaneous (s.c.)] were administered to shrews 10 min prior to an injection of a fully effective antiemetic dose of Delta(9)-THC (5 mg/kg, i.p.). Ten minutes later, each treated shrew was administered with a 2 mg/kg dose of apomorphine. The emesis frequency was recorded for the next 30 min. For locomotor studies, different groups of shrews received either vehicle or various doses of Delta(9)-THC (0, 5, 10, 20, or 30mg/kg) 10 min prior to an injection of vehicle or a 2 mg/kg dose of one of the four D2/D3 receptor agonists. The triad of motor behaviors (spontaneous locomotor activity, total duration of movement, and rearing frequency) were recorded for the next 30 min by a computerized video tracking system. Delta(9)-THC dose-dependently attenuated the frequency of emesis as well as fully protecting shrews from vomiting produced by each one of the four cited dopamine D2/D3 receptor agonists with ID50s ranging from 1 to 4 mg/kg. SR 141716A reversed the antiemetic activity of Delta(9)-THC against apomorphine-induced emesis. Delta(9)-THC also differentially suppressed the triad of motor activities in dopamine D2/D3-receptor-agonist-treated shrews with ID50s, ranging from 7 to 21 mg/kg. The results suggest that Delta(9)-THC prevents emesis via cannabinoid CB1 receptors in a potent and dose-dependent manner in D-2/D-3-receptor-agonist-treated shrews at doses well below those which cause significant motor depression. (C) 2004 Elsevier Inc. All rights reserved.