Zádor Ferenc, Lénárt Nikolett, Csibrány Balázs, Sántha Miklós, Molnár Máté, Tuka Bernadett, Samavati Reza, Klivényi Péter, Vécsei László, Marton Annamária, Vizler Csaba, Nagy György M, Borsodi Anna, Benyhe Sándor, Páldy Eszter
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt. 62, H-6726 Szeged,Hungary.
Neuropharmacology. 2015 Feb;89:298-307. doi: 10.1016/j.neuropharm.2014.10.008.
There is an increasing number of studies demonstrating the direct effect of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant on the opioid system. The kappa opioid receptors (KORs) are well known to mediate depression- and anxiety-like behavior. Clinical studies on chronic rimonabant administration have revealed that rimonabant leads to a very similar pathophysiology, suggesting a potential impact of rimonabant on KORs.
Our objectives were to examine the putative effects of rimonabant on KOR ligand binding, G-protein activity, protein expression and how all these contribute to the development of depression- and anxiety-like behavior.
In Chinese hamster ovary (CHO) cell membranes transfected with rat KOR (CHO-rKOR) rimonabant inhibited KOR agonist [3H]U69593 binding in the micromolar range in competition binding experiments and specifically reduced KOR basal activity at lower micromolar concentrations in [35S]GTPγS binding assays. Rimonabant significantly inhibited dynorphin (1-11)-induced [35S]GTPγS binding in micromolar range in CHO-rKOR cells, CB1 knockout (CB1 K.O.) and CB1/CB2 double knockout mouse forebrain membranes. A single dose of i.p. 0.1 mg/kg rimonabant significantly reduced dynorphin (1-11)-induced KOR G-protein activity and KOR protein expression levels 24 h following the administration in both wild type and CB1 K.O. mice forebrain. Furthermore, in elevated plus maze mice showed an anxiolytic-like effect upon rimonabant injection that could be reversed by 1 mg/kg KOR antagonist norbinaltorphimine. The anxiolytic-like effects were further confirmed with the light–dark box test.
Rimonabant reduced KOR ligand binding, receptor mediated G-protein activity and protein expression level, which overall leads to altered anxiety-like behavior.
越来越多的研究表明，大麻素受体1（CB1）拮抗剂/反向激动剂利莫那班对阿片系统有直接作用。众所周知，κ阿片受体（KORs）介导抑郁样和焦虑样行为。关于长期服用利莫那班的临床研究表明，利莫那班导致非常相似的病理生理学，提示利莫那班对KORs有潜在影响。
我们的目的是研究利莫那班对KOR配体结合、G蛋白活性、蛋白表达的假定作用，以及所有这些如何导致抑郁样和焦虑样行为的发生。
在用大鼠KOR转染的中国仓鼠卵巢（CHO）细胞膜（CHO-rKOR）中，在竞争结合实验中，利莫那班在微摩尔范围内抑制KOR激动剂[3H]U69593结合，并且在[35S]GTPγS结合试验中，在较低微摩尔浓度下特异性降低KOR基础活性。在CHO-rKOR细胞、CB1基因敲除（CB1 K.O.）和CB1/CB2双基因敲除小鼠前脑细胞膜中，利莫那班在微摩尔范围内显著抑制强啡肽（1-11）诱导的[35S]GTPγS结合。腹腔注射0.1mg/kg利莫那班单次剂量，在野生型和CB1 K.O.小鼠前脑中给药24小时后，显著降低强啡肽（1-11）诱导的KOR G蛋白活性和KOR蛋白表达水平。此外，在高架十字迷宫实验中，小鼠注射利莫那班后表现出抗焦虑样作用，该作用可被1mg/kg KOR拮抗剂诺宾阿尔托啡因逆转。明暗箱试验进一步证实了抗焦虑样作用。
利莫那班降低KOR配体结合、受体介导的G蛋白活性和蛋白表达水平，总体上导致焦虑样行为改变。
