Central functional response to the novel peptide cannabinoid, hemopressin
Central functional response to the novel peptide cannabinoid, hemopressin
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DOI：
10.1016/j.neuropharm.2013.03.007
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发表时间：
2013-08-01
影响因子：
4.7
通讯作者：
Luckman, Simon M.
中科院分区：
文献类型：
--
作者：
Dodd, Garron T.;Worth, Amy A.;Luckman, Simon M.
加压素是第一个肽配体被描述为CB1大麻素受体。在体内，加压素作为一种逆激动剂，可以穿过血脑屏障，抑制食欲和诱导抗感觉。尽管是高度有效的，合成CB1逆激动剂是有限的治疗由于不必要的，过度抑制中枢奖励途径。然而，加压素似乎是通过影响饱腹感而不是奖励来影响食欲的，这提示了一种可能避免不良副作用的替代作用模式。在这里，为了解决介导加压素作用的神经回路，我们将血氧水平依赖性，药物学挑战磁共振成像与c-Fos功能活动作图相结合，比较脑区域对全身给药加压素和合成CB1逆激动剂AM251的反应。使用这些互补的方法，我们证明了加压素激活大脑内不同的神经元底物，主要集中在下丘脑中基底部的喂食相关回路以及导管周围灰质（PAG）和中叶背（DR）的伤害性区域。与AM251相比，AM251明显缺乏大脑奖励中心的激活，如腹侧被盖区、伏隔核和眶额皮质，这些区域通常形成合成CB1受体逆激动剂中枢作用的功能活动特征。因此，加压素调节的是下丘脑中基底部与进食相关的关键脑核的功能，以及PAG和DR的下行疼痛通路，而不是高级边缘结构。因此，加压素可能对伤害感觉和食欲提供行为选择性影响，而不参与奖励途径。(C) 2013 Elsevier Ltd.版权所有。
Hemopressin is the first peptide ligand to be described for the CB1 cannabinoid receptor. Hemopressin acts as an inverse agonist in vivo and can cross the blood brain barrier to both inhibit appetite and induce antinociception. Despite being highly effective, synthetic CB1 inverse agonists are limited therapeutically due to unwanted, over dampening of central reward pathways. However, hemopressin appears to have its effect on appetite by affecting satiety rather than reward, suggesting an alternative mode of action which might avoid adverse side effects. Here, to resolve the neuronal circuitry mediating hemopressin's actions, we have combined blood-oxygen-level-dependent, pharmacological-challenge magnetic resonance imaging with c-Fos functional activity mapping to compare brain regions responsive to systemic administration of hemopressin and the synthetic CB1 inverse agonist, AM251. Using these complementary methods, we demonstrate that hemopressin activates distinct neuronal substrates within the brain, focused mainly on the feeding-related circuits of the mediobasal hypothalamus and in nociceptive regions of the periaqueductal grey (PAG) and dorsal raphe (DR). In contrast to AM251, there is a distinct lack of activation of the brain reward centres, such as the ventral tegmental area, nucleus accumbens and orbitofrontal cortex, which normally form a functional activity signature for the central action of synthetic CB1 receptor inverse agonists. Thus, hemopressin modulates the function of key feeding-related brain nuclei of the mediobasal hypothalamus, and descending pain pathways of the PAG and DR, and not higher limbic structures. Thus, hemopressin may offer behaviourally selective effects on nociception and appetite, without engaging reward pathways. (C) 2013 Elsevier Ltd. All rights reserved.