Economidou D, Fedeli A, Fardon R Martin, Weiss F, Massi M, Ciccocioppo R
Department of Experimental Medicine and Public Health, University of Camerino, Via Scalzino 3, 62032 Camerino, MC, Italy.
Peptides. 2006 Dec;27(12):3299-306. doi: 10.1016/j.peptides.2006.09.007.
Activation of the NOP receptor by the endogenous ligand nociceptin/orphanin FQ (N/OFQ) reduces alcohol consumption in genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The present study evaluated the effect of three newly synthesized peptidergic and one brain-penetrating heterocyclic NOP receptor agonists on alcohol drinking in the two bottle choice paradigm. MsP rats were intracerebroventricularly (ICV) injected with the NOP receptor agonists OS-462 (0.5 and 1.0 microg), UFP-102 (0.25 and 1.0 microg) or UFP-112 (0.01 and 0.05 microg), or with Ro 64-6198 (0.3 and 1.0 mg/kg) given intraperitoneally (i.p.) and tested for 10% alcohol consumption. Results showed decreased alcohol consumption after treatment with all three peptidergic NOP receptor agonists (OS-462, UFP-102 and UFP-112). OS-462 (at the 1.0 microg dose) and UFP-102 (at the 0.25 microg dose) induced a significant increase in food intake as well. Surprisingly, Ro 64-6198 was ineffective at the 0.3 mg/kg dose, whereas it increased ethanol and food consumption at the 1.0 mg/kg dose. Pre-treatment with the selective mu-receptor antagonist naloxone (0.5 mg/kg, i.p.) reduced these effects of 1.0 mg/kg of Ro 64-6198. These findings confirm that activation of brain NOP receptors reduces alcohol drinking in msP rats and demonstrate that OS-462, UFP-102 and UFP-112 act as potent NOP receptor agonists. On the other hand, Ro 64-6198 increased alcohol drinking, an effect probably induced by a residual agonist activity of this compound at mu-opioid receptors. Overall, the results indicate that OS-462, UFP-102 and UFP-112 may represent valuable pharmacological tools to investigate the functional role of the brain N/OFQ system.
内源性配体痛敏肽/孤啡肽FQ（N/OFQ）激活NOP受体可减少基因选择的嗜酒马尔基安撒丁岛（msP）大鼠的酒精摄入量。本研究在双瓶选择范式中评估了三种新合成的肽能和一种可穿透脑的杂环NOP受体激动剂对酒精饮用的影响。给msP大鼠脑室内（ICV）注射NOP受体激动剂OS-462（0.5和1.0微克）、UFP-102（0.25和1.0微克）或UFP-112（0.01和0.05微克），或腹腔内（i.p.）注射Ro 64-6198（0.3和1.0毫克/千克），并测试其对10%酒精摄入量的影响。结果显示，用所有三种肽能NOP受体激动剂（OS-462、UFP-102和UFP-112）治疗后酒精摄入量减少。OS-462（1.0微克剂量）和UFP-102（0.25微克剂量）也显著增加了食物摄入量。令人惊讶的是，Ro 64-6198在0.3毫克/千克剂量时无效，而在1.0毫克/千克剂量时增加了乙醇和食物摄入量。用选择性μ受体拮抗剂纳洛酮（0.5毫克/千克，i.p.）预处理可降低1.0毫克/千克Ro 64-6198的这些作用。这些发现证实脑NOP受体的激活可减少msP大鼠的酒精饮用，并表明OS-462、UFP-102和UFP-112可作为有效的NOP受体激动剂。另一方面，Ro 64-6198增加了酒精饮用，这种作用可能是由该化合物在μ阿片受体上的残留激动剂活性诱导的。总体而言，结果表明OS-462、UFP-102和UFP-112可能是研究脑N/OFQ系统功能作用的有价值的药理学工具。
