Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis
Central and peripheral mechanisms contribute to the antiemetic actions of delta-9-tetrahydrocannabinol against 5-hydroxytryptophan-induced emesis
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DOI：
10.1016/j.ejphar.2004.02.018
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发表时间：
2004-03-19
影响因子：
5
通讯作者：
Johnson, JC
中科院分区：
文献类型：
--
作者：
Darmani, NA;Johnson, JC
Delta-9-tetrahydrocannabinol（delta-9-THC）通过大麻素CB 1受体防止顺铂诱导的呕吐。中枢和/或外周大麻素CB 1受体是否解释了δ-9-THC的止吐作用仍有待研究。5-羟色胺（5-HT= 5-羟色胺）的前体5-羟色氨酸（5-HTP）是一种间接的5-HT激动剂，在小鼩（Cryptotis parva）中同时产生头部抽搐反应（中枢介导的5-羟色胺5-HT 2A受体诱导的行为）和呕吐（由外周和中枢机制介导的5-羟色胺5-HT 3受体诱导的反应）。外周氨基酸脱羧酶抑制剂卡比多巴阻止外周中5-HTP转化为5-HT，并升高中枢神经系统（CNS）中的5-HTP水平。当单独腹膜内给药时，50 mg/kg剂量的5-HTP未能诱导任何一种行为，而其100 mg/kg剂量产生强烈的头部抽搐反应和呕吐频率。用卡比多巴（0、10、20和40 mg/kg）预处理增强了两种剂量的5-HTP以剂量依赖性但钟形方式产生头部抽搐反应的能力，其中最大增强发生在20 mg/kg卡比多巴。卡比多巴剂量依赖性地降低5-HTP（100 mg/kg）诱导的呕吐频率，而10 mg/kg剂量增强，20和40 mg/kg剂量抑制50 mg/kg剂量的5-HTP产生的呕吐频率。在卡比多巴（0、10和20 mg/kg）预处理的不同组中，研究了δ-9-THC（0、1、2.5、5、10和20 mg/kg）对5-HTP（100 mg/kg）诱导的头部抽动反应和呕吐的外周和/或中枢止吐作用。不考虑卡比多巴治疗，δ-9-THC以剂量依赖性方式减弱5-HT诱导的头部抽搐反应的频率，具有相似的ID 50值。尽管δ-9-THC也降低了5-HTP诱导的呕吐的频率，在5 mg/kg δ-9-THC剂量下具有相似的ID 50，但是，相对于其0 mg/kg对照组，5-HTP在10和20 mg/kg卡比多巴治疗组中诱导的呕吐显著较少。此外，卡比多巴剂量的增加显著地将δ-9-THC在保护大鼠免于5-HT诱导的呕吐中的抑制剂量-反应效应向左偏移。相对地，需要大剂量的δ-9-THC（20 mg/kg）来显著减少由直接作用的肾上腺素能5-HT 3受体激动剂、5-羟色胺和2-甲基5-羟色胺产生的呕吐的数量。低剂量的δ-9-THC（0.1-1 mg/kg）几乎完全防止了2 -甲基5-羟色胺诱导的中枢介导的头部抽搐和抓耳反应。结果表明，δ-9-THC可能通过中枢和外周机制在突触前和突触后起作用，以减轻由间接和直接作用的5-HT 3受体激动剂产生的呕吐。此外，δ-9-THC通过大麻素CB 1受体防止5-HT诱导的头部抽搐和呕吐，因为CB 1受体拮抗剂SR 141716 A [N-哌啶基-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基吡唑-3-甲酰胺]抵消了有效剂量的δ-9-THC对这两种行为的抑制作用。(C)2004 Elsevier B. V.保留所有权利。
Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB1 receptors. Whether central and/or peripheral cannabinoid CB1 receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the head-twitch response (a centrally mediated serotonin 5-HT2A receptor-induced behavior) and emesis (a serotonin 5-HT3 receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both head-twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the head-twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced head-twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews. Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced head-twitch response in a dose-dependent manner with similar ID50 values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID50 at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose-response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT3 receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1-1 mg/kg) nearly completely prevented 2 -methylserotonin -induced, centrally mediated, head-twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT3 receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced head-twitch and emesis via cannabinoid CB1 receptors since the CB1 receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours. (C) 2004 Elsevier B.V. All rights reserved.