Combined blockade of both μ- and κ-opioid receptors prevents the acute orexigenic action of agouti-related protein
Combined blockade of both μ- and κ-opioid receptors prevents the acute orexigenic action of agouti-related protein
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DOI：
10.1210/en.2002-220230
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发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
Seeley, RJ
中科院分区：
文献类型：
--
作者：
Brugman, S;Clegg, DJ;Seeley, RJ
Agouti-related protein（AgRP）是下丘脑黑皮质素3和4受体的内源性拮抗剂。AgRP的中枢给药产生了强烈的食物摄入量增加，这种作用可以被非特异性阿片受体拮抗剂阻断。这些结果暗示阿片受体对介导AgRP的作用至关重要。为了确定哪种阿片受体亚型是关键的，我们首先确定了两种特异性阿片受体拮抗剂的最高i3 vt（给药至第三脑室）剂量，即去甲-比那托啡或β-funaltorphine，它们本身不会影响食物摄入。然后，在i3 vt AgRP之前用这两种拮抗剂中的任一种预处理大鼠并获得高脂肪饮食。对于κ-或μ-特异性拮抗剂，没有任何作用来阻断AgRP对食物摄取的作用。然而，kappa-和mu-受体拮抗剂两者的施用确实显著降低AgRP的作用。目前的结果暗示阿片受体作为AgRP增加食物摄入的有效作用的关键下游介质，但表明μ-或κ-受体活化足以实现AgRP的作用。
Agouti-related protein (AgRP) is an endogenous antagonist at the melanocortin 3 and 4 receptor in the hypothalamus. Central administration of AgRP produces a robust increase in food intake, and this effect can be blocked by administration of nonspecific opioid receptor antagonist. Such results implicate opioid receptors as critical to mediating the effects of AgRP. To determine which opioid receptor subtype is critical, we first determined the highest i3vt (administered into the third ventricle) dose of two specific opioid antagonists, nor-Binaltorphine or beta-funaltrexamine, that did not influence food intake on their own. Then, rats were pretreated with either of these two antagonists before i3vt AgRP and access to a high-fat diet. For neither the kappa- nor the mu-specific antagonist was there any effect to block the effects of AgRP on food intake. However, administration of both the kappa- and mu-receptor antagonists does significantly reduce the effect of AgRP. The current results implicate opioid receptors as critical downstream mediators of the potent effects of AgRP to increase food intake but indicate that either mu- or kappa-receptor activation is sufficient for AgRP's effect.