The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen
The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen
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DOI：
10.1073/pnas.0404366101
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发表时间：
2004-08-10
影响因子：
11.1
通讯作者：
Rettori, V
中科院分区：
文献类型：
--
作者：
Scorticati, C;Fernández-Solari, J;Rettori, V
由于Delta-9-tetrahydrocannabinol（THC）抑制雄性大鼠的促黄体生成激素释放激素（LHRH），我们假设内源性大麻素anandamide（AEA）也会起类似作用。侧脑室微量注射AEA（i. c. v.）与对照组相比，30分钟时血浆促黄体生成素（LH）降低（P < 0.001）。大麻素受体1（CB 1-r）特异性拮抗剂[N-（哌啶-1-基）-1-（2，4-二氯苯基）-5-（4-氯苯基）-4-甲基-1wH-吡唑-3-甲酰胺]（AM 251）可显著升高血浆LH（P < 0.01）。AEA（10（-9）M）可抑制离体培养的下丘脑基底内侧核LHRH的释放。这些结果支持内源性AEA抑制LHRH，然后减少LH释放的概念。在卵巢切除（OVX）雌性大鼠中，AEA i. c. v.也抑制LH释放，但在这种情况下，AM 251的抑制作用甚至比AEA更大。体外实验表明，AEA对去卵巢大鼠LHRH无影响。似乎内源性AEA抑制LHRH，随后减少OVX大鼠LH释放，但AM 251在这种情况下具有抑制作用。与此形成鲜明对比的是，在OVX，雌激素致敏（OVX-E）大鼠，AEA i. c. v.，而不是减少LH，增加其释放。这种作用被先前注射的AM 251完全阻断。AEA可增加OVX-E大鼠下丘脑内侧基底核LHRH的释放。合成的AEA在OVX-E大鼠高于OVX和男性，表明雌激素改变内源性大麻素的水平和影响。这些结果被解释为意味着性类固醇对改变对AEA的反应具有深远的影响。它抑制LHRH，从而减少LH释放的男性和OVX女性，但刺激LHRH随后增加LH释放的OVX-E-致敏大鼠。
Because Delta-9-tetrahydrocannabinol (THC) inhibited luteinizing hormone-releasing hormone (LHRH) in male rats, we hypothesized that the endocannabinoid, anandamide (AEA), would act similarly. AEA microinjected intracerebroventricularly (i.c.v.) decreased plasma luteinizing hormone (LH) at 30 min in comparison to values in controls (P < 0.001). The cannabinoid receptor 1 (CB1-r)-specific antagonist, [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1wH-pyrazole-3-carboxamide] (AM251), produced a significant elevation in plasma LH (P < 0.01). AEA (10(-9) M) decreased LHRH release from medial basal hypothalami incubated in vitro. These results support the concept that endogenous AEA inhibits LHRH followed by decreased LH release in male rats. In ovariectomized (OVX) female rats, AEA i.c.v. also inhibited LH release, but in this case AM251 had an even greater inhibitory effect than AEA. In vitro, AEA had no effect on LHRH in OVX rats. It seems that endogenous AEA inhibits LHRH followed by decreased LH release in OVX rats but that AM251 has an inhibitory action in this case. In striking contrast, in OVX, estrogen-primed (OVX-E) rats, AEA i.c.v. instead of decreasing LH, increased its release. This effect was completely blocked by previous injection of AM251. When medial basal hypothalami of OVX-E rats were incubated, AEA increased LHRH release. The synthesized AEA was higher in OVX-E rats than in OVX and males, indicating that estrogen modifies endocannabinoid levels and effects. The results are interpreted to mean that sex steroids have profound effects to modify the response to AEA. It inhibits LHRH and consequently diminishes LH release in males and OVX females, but stimulates LHRH followed by increased LH release in OVX-E-primed rats.