Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice:: evidence for a "CB3" receptor
Milk intake and survival in newborn cannabinoid CB1 receptor knockout mice:: evidence for a "CB3" receptor
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DOI：
10.1016/s0014-2999(03)01295-0
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发表时间：
2003-02-07
影响因子：
5
通讯作者：
Mechoulam, R
中科院分区：
文献类型：
--
作者：
Fride, E;Foox, A;Mechoulam, R
大麻素，无论是植物衍生的，合成的还是内源性的，都已被证明能刺激成年生物体的食欲。我们以前曾报道过大麻素受体在早期哺乳期起着关键作用：选择性大麻素CB 1受体拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（SR 141617 A）在出生后1天内给予（Sabra，白化病）小鼠幼仔时，以剂量依赖性方式永久性阻止乳汁摄入。结果，这些幼崽在出生后的第一周内死亡。我们现在将这一发现推广到不同的小鼠品系（C57 BL/6）。此外，我们表明，大麻素CB 1受体阻滞剂（20 mg/kg SR 141716 A）必须在出生后24小时内发生，因为将SR 141716 A注射到2或5日龄幼仔中分别具有小得多的影响或根本没有影响。大麻素CB I受体敲除小鼠在出生后第一天未摄入乳汁，与SR 141716 A给药的正常幼仔相似，通过“乳带”外观进行测量。然而，敲除幼仔从出生后第2天开始出现乳带。大麻素CB 1受体敲除小鼠的存活率受到SR 141716 A给药的显著影响，但程度低于正常幼仔。每日施用内源性大麻素2-花生四烯酸甘油或合成激动剂（R）-（+）-[2，3-二氢-5-甲基-3-（三氟甲基）苯基]-N-甲基-N-（三氟甲基）苯基]-N-（三氟甲基）苯基-N（4-吗啉基甲基）吡咯并[1，2，3-de]-1，4-苯并恶嗪-6-基]-1-萘基乙基化（WIN 55，212-2，5 mg/kg）或（-）-顺式-3-[2-羟基-4-（1，1-二甲基庚基）苯基]-反式-4-（3-羟丙基）环己醇（CP 55、940、5或20 mg/kg）未促进CB 1-/-幼仔的存活或体重增加。我们的数据支持以前的证据大麻素CB 1受体的关键作用，开始吸吮。此外，目前的观察结果支持存在未知的大麻素受体，部分控制新生儿的牛奶摄入。我们的数据还表明，CB 1-/-新生儿具有代偿机制，有助于他们克服大麻素CB 1受体的缺乏。(C)2003 Elsevier Science B. V.保留所有权利。
Cannabinoids, whether plant-derived, synthetic or endogenous, have been shown to stimulate appetite in the adult organism. We have reported previously that cannabinoid receptors play a critical role during the early suckling period: The selective cannabinoid CB1 receptor antagonist N-(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-IH-pyrazole-3-carboxamide (SR141617A) permanently prevented milk ingestion in a dose-dependent manner, when administered to (Sabra, albino) mouse pups, within I day of birth. As a consequence, these pups died within the first week of life. We now generalize this finding to a different strain of mice (C57BL/6). Further, we show that cannabinoid CB1 receptor blockade (20 mg/kg SR141716A) must occur within 24 h after birth as injection of SR141716A into 2-or 5-day-old pups had a much smaller effect or no effect at all, respectively. Cannabinoid CB I receptor knockout mice did not ingest milk on the first day of life, similarly to SR141716A-treated normal pups, as measured by the appearance of "milkbands". However, the knockout pups started to display milkbands from day 2 of life. Survival rates of cannabinoid CB1 receptor knockout mice were affected significantly, but to a lesser extent than normal pups, by the administration of SR141716A. Daily administration of the endocannabinoid 2-arachidonoyl glycerol, or the synthetic agonists (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylinethatione (WIN55,212-2, 5 mg/kg) or (-)-cis-3-[2-Hydroxy4-(1,1-dimethylheptyl) phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940, 5 or 20 mg/kg) did not promote survival or weight gain in CB1-/- pups. Our data support previous evidence for a critical role of cannabinoid CB1 receptors for the initiation of suckling. Further, the present observations support the existence of an unknown cannabinoid receptor, with partial control over milk ingestion in newborns. Our data also suggest that the CB1-/- neonates possess a compensatory mechanism which helps them overcome the lack of cannabinoid CB1 receptors. (C) 2003 Elsevier Science B.V. All rights reserved.