Laboratorio de Fisiología y Farmacología de Reproducción, CEFYBO (CONICET-UBA), Paraguay 2155, 16th floor, CP (C1121ABG), Buenos Aires, Argentina.
Eur J Pharmacol. 2012 Jun 15;685(1-3):174-9. doi: 10.1016/j.ejphar.2012.04.034. Epub 2012 Apr 25.
Anandamide, an endocannabinoid, prostaglandins derived from cyclooxygenase-2 and nitric oxide synthesized by nitric oxide synthase (NOS), are relevant mediators of embryo implantation. We adopted a pharmacological approach to investigate if anandamide modulated NOS activity in the receptive rat uterus and if prostaglandins mediated this effect. As we were interested in studying the changes that occur at the maternal side of the fetal-maternal interface, we worked with uteri obtained from pseudopregnant rats. Females were sacrificed on day 5 of pseudopregnancy, the day in which implantation would occur, and the uterus was obtained. Anandamide (2 ng/kg, i.p.) inhibited NOS activity (P<0.001) and increased the levels of prostaglandin E(2) (P<0.001) and prostaglandin F(2α) (P<0.01). These effects were mediated via cannabinoid receptor type 2, as the pre-treatment with SR144528 (10 mg/kg, i.p.), a selective cannabinoid receptor type 2 antagonist, completely reverted anandamide effect on NOS activity and prostaglandin levels. The pre-treatment with a non-selective cyclooxygenase inhibitor (indomethacin 2.5mg/kg, i.p.) or with selective cyclooxygenase-2 inhibitors (meloxicam 4 mg/kg, celecoxib 3mg/kg, i.p.) reverted anandamide inhibition on NOS, suggesting that prostaglandins are derived from cyclooxygenase-2 mediated anandamide effect. Thus, anandamide levels seemed to modulate NOS activity, fundamental for implantation, via cannabinoid receptor type 2 receptors, in the receptive uterus. This modulation depends on the production of cyclooxygenase-2 derivatives. These data establish cannabinoid receptors and cyclooxygenase enzymes as an interesting target for the treatment of implantation deficiencies.
内源性大麻素，前列腺素，来源于环氧化酶-2 和一氧化氮合酶（NOS）合成的一氧化氮，是胚胎着床的相关介质。我们采用药理学方法来研究内源性大麻素是否调节接受态大鼠子宫中的 NOS 活性，以及前列腺素是否介导这种作用。因为我们对研究胎儿-母体界面母体侧发生的变化感兴趣，所以我们使用了来自假孕大鼠的子宫。雌性大鼠在假孕第 5 天（即着床日）被处死，并取出子宫。内源性大麻素（2ng/kg，腹腔注射）抑制 NOS 活性（P<0.001）并增加前列腺素 E2（P<0.001）和前列腺素 F2α（P<0.01）的水平。这些作用是通过大麻素受体 2 介导的，因为用选择性大麻素受体 2 拮抗剂 SR144528（10mg/kg，腹腔注射）预处理完全逆转了内源性大麻素对 NOS 活性和前列腺素水平的作用。用非选择性环氧化酶抑制剂（吲哚美辛 2.5mg/kg，腹腔注射）或选择性环氧化酶-2 抑制剂（美洛昔康 4mg/kg，塞来昔布 3mg/kg，腹腔注射）预处理可逆转内源性大麻素对 NOS 的抑制作用，表明前列腺素来源于环氧化酶-2 介导的内源性大麻素作用。因此，内源性大麻素水平似乎通过大麻素受体 2 受体调节接受态子宫中对植入至关重要的 NOS 活性。这种调节依赖于环氧化酶-2 衍生物的产生。这些数据确立了大麻素受体和环氧化酶酶作为治疗植入缺陷的一个有趣的靶点。
