Khroyan Taline V, Polgar Willma E, Jiang Faming, Zaveri Nurulain T, Toll Lawrence
Policy Division, SRI International, Menlo Park, California 94025, USA.
J Pharmacol Exp Ther. 2009 Dec;331(3):946-53. doi: 10.1124/jpet.109.156711. Epub 2009 Aug 27.
Activation of brain nociceptin/orphanin FQ (NOP) receptors leads to attenuation of mu-opioid receptor (MOP receptor)-mediated antinociception. Buprenorphine, a high-affinity partial MOP receptor agonist also binds to NOP receptors with 80 nM affinity. The buprenorphine-induced inverted U-shaped dose-response curve for antinociception may be due to NOP receptor activation, given that, in the presence of the NOP receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J113397), or in NOP receptor knockout mice, buprenorphine has a steeper dose-response curve and acts as a full agonist. To further explore the involvement of the direct activation of NOP receptors by buprenorphine and other compounds that activate both NOP and MOP receptors, the antinociceptive effects of 1-(1-(2,3,3alpha,4,5,6-hexahydro-1H-phenalen-1-yl)piperidin-4-yl)-indolin-2-one. (SR16435), 3-ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin-2-one (SR16507), buprenorphine, pentazocine, and morphine, compounds with varying levels of MOP and NOP receptor affinity and efficacy, were assessed in mice using the tail-flick assay. The ability of the selective NOP receptor antagonist (-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol (SB-612111) to potentiate antinociception induced by the above compounds was examined to investigate whether activation of NOP receptors leads to attenuation of MOP receptor-mediated antinociception. SB-612111 potentiated antinociception induced by buprenorphine and the other mixed NOP/MOP receptor agonists SR16435 and SR16507. However, SB-612111 had no effect on pentazocine or morphine antinociception, two compounds with no NOP receptor-binding affinity. These results further support the hypothesis that activation of NOP receptors can lead to attenuation of MOP receptor-mediated antinociception elicited by mixed NOP/MOP receptor compounds such as buprenorphine, SR16435, and SR16507 and that, although buprenorphine has low efficacy in vitro, it has significant NOP receptor agonist activity in vivo.
脑内孤啡肽/孤啡肽FQ（NOP）受体的激活会导致μ-阿片受体（MOP受体）介导的镇痛作用减弱。丁丙诺啡是一种高亲和力的部分MOP受体激动剂，它也能以80 nM的亲和力与NOP受体结合。丁丙诺啡诱导的镇痛作用呈倒U形剂量反应曲线，这可能是由于NOP受体的激活，因为在存在NOP受体拮抗剂1-[(3R,4R)-1-环辛基甲基-3-羟甲基-4-哌啶基]-3-乙基-1,3-二氢-2H-苯并咪唑-2-酮（J113397）的情况下，或者在NOP受体基因敲除小鼠中，丁丙诺啡具有更陡峭的剂量反应曲线并表现为完全激动剂。为了进一步探究丁丙诺啡以及其他同时激活NOP和MOP受体的化合物对NOP受体的直接激活作用，使用甩尾试验评估了1-(1-(2,3,3α,4,5,6-六氢-1H-菲-1-基)哌啶-4-基)-吲哚啉-2-酮（SR16435）、3-乙基-1-(1-(4-异丙基环己基)哌啶-4-基)-吲哚啉-2-酮（SR16507）、丁丙诺啡、喷他佐辛和吗啡这些具有不同水平MOP和NOP受体亲和力及效能的化合物在小鼠中的镇痛作用。研究了选择性NOP受体拮抗剂(-)-顺式-1-甲基-7-[[4-(2,6-二氯苯基)哌啶-1-基]甲基]-6,7,8,9-四氢-5H-苯并环庚烯-5-醇（SB-612111）增强上述化合物诱导的镇痛作用的能力，以研究NOP受体的激活是否会导致MOP受体介导的镇痛作用减弱。SB-612111增强了丁丙诺啡以及其他混合NOP/MOP受体激动剂SR16435和SR16507诱导的镇痛作用。然而，SB-612111对喷他佐辛或吗啡的镇痛作用没有影响，这两种化合物没有NOP受体结合亲和力。这些结果进一步支持了以下假设：NOP受体的激活可导致由丁丙诺啡、SR16435和SR16507等混合NOP/MOP受体化合物引发的MOP受体介导的镇痛作用减弱，并且尽管丁丙诺啡在体外效能较低，但它在体内具有显著的NOP受体激动剂活性。
