Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect
Nociceptin/orphanin FQ acts as a functional antagonist of corticotropin-releasing factor to inhibit its anorectic effect
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DOI：
10.1016/j.physbeh.2004.04.035
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发表时间：
2004-08-01
影响因子：
2.9
通讯作者：
Massi, M
中科院分区：
文献类型：
--
作者：
Ciccocioppo, R;Cippitelli, A;Massi, M
孤啡肽/孤啡肽FQ（N/OFQ）是NOP阿片受体（以前称为ORL 1或OP 4受体）的内源性配体，发挥多种行为效应。N/OFQ以及合成的NOP受体激动剂Ro 64-6198已被报道具有抗应激特性，并在自由喂养的大鼠中引起显著的摄食过量效应。这些发现引起了我们的兴趣，调查可能的相互作用，在控制摄食行为之间的N/OFQ和促肾上腺皮质激素释放因子（CRF），这是众所周知的是一个主要的调解人的压力，并具有厌食的属性。这些研究表明，脑室内注射N/OFQ或Ro 64-6198可逆转脑室内注射CRF引起的厌食作用。N/OFQ或Ro 64-6198的抗厌食作用被选择性NOP受体拮抗剂[Nphe（1）]N/OFQ（1-13）NH 2拮抗，这提供了它由该受体介导的证据。这种作用发生在本身不具有超噬作用的剂量下，并且与CRF的厌食作用相比具有明显的选择性，因为N/OFQ或Ro 64-6198不影响大肠杆菌脂多糖（LPS）的厌食作用。N/OFQ和Ro 64-6198均不显示对CRT受体的亲和力，表明NOP受体激动剂可能在其厌食作用方面作为CRF的功能性拮抗剂。显微注射研究表明，终纹床核（BNST）对CRF的厌食作用以及N/OFQ的抗厌食作用高度敏感;用0.025-0.25 μ g/部位的N/OFQ预处理BNST可阻断在同一区域给予0.1 μ g/部位的CRF的厌食作用。另一方面，BNST内微量注射0.025-0.25 μ g/部位的N/OFQ并没有改变基础食物摄入量。因此，BNST可能是N/OFQ和CRF之间发生功能性拮抗作用的部位。这些发现引起了对N/OFQ-NOP受体系统作为阻断CRE的厌食作用的药理学靶点的兴趣。与CRF受体拮抗剂相比，NOP受体激动剂可能具有不抑制下丘脑-垂体-肾上腺（HPA）轴的优点。(C)2004年爱思唯尔公司All rights reserved.
Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor (previously referred to as ORL1 or OP4 receptor), exerts a variety of behavioral effects. N/OFQ as well as the synthetic NOP receptor agonist Ro 64-6198 have been reported to possess antistress properties and to elicit a pronounced hyperphagic effect in freely feeding rats. These findings have raised our interest to investigate possible interactions in the control of ingestive behavior between N/OFQ and corticotropin-releasing factor (CRF), which is well known to be a major mediator of stress and to possess anorectic properties. These studies have shown that intracerebroventricular injections of N/OFQ or of Ro 64-6198 reverse the anorectic action evoked by intracerebroventricular administration of CRF. The anti-anorectic effect of N/OFQ or Ro 64-6198 is antagonized by the selective NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH2, providing evidence that it is mediated by this receptor. The effect occurs at doses that are not hyperphagic per se and is clearly selective versus the anorectic action of CRF since N/OFQ or Ro 64-6198 do not influence the anorectic effect of Escherichia coli lipopolysaccharide (LPS). Neither N/OFQ nor Ro 64-6198 shows affinity for CRT receptors, suggesting that NOP receptor agonists might act as functional antagonists of CRF with regard to its anorectic action. Microinjection studies have revealed that the bed nucleus of the stria terminalis (BNST) is highly sensitive to the anorectic action of CRF, as well as to the anti-anorectic action of N/OFQ; pretreatment with 0.025-0.25 mug/site of N/OFQ into the BNST blocked the anorectic action of 0.1 mug/site of CRF given in the same area. On the other hand, intra-BNST microinjection of 0.025-0.25 mug/site of N/OFQ did not modify basal food intake. Thus, the BNST may be the site where the functional antagonism between N/OFQ and CRF takes place. These findings raise interest for the N/OFQ-NOP receptor system as a pharmacological target to block the anorectic effect of CRE In comparison to CRF receptor antagonists, NOP receptor agonists may have the advantage of not inhibiting the hypothalamic -pituitary -adrenal (HPA) axis. (C) 2004 Elsevier Inc. All rights reserved.