SRI International, Menlo Park, California, USA.
J Pharmacol Exp Ther. 2011 Nov;339(2):687-93. doi: 10.1124/jpet.111.184663. Epub 2011 Aug 22.
1-(1-Cyclooctylpiperidin-4-yl)-indolin-2-one (SR14150) and 1-(1-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835) are moderately selective nociceptin/orphanin FQ (NOP) receptor agonists. In the [(35)S]guanosine 5'-O-(3-thiotriphosphate) assay in vitro, SR14150 is a partial agonist at both the NOP and μ-opioid receptors, whereas SR16835 is a full agonist at the NOP receptor and has low efficacy at μ receptors. These compounds were tested for antinociceptive and antiallodynic activity, using mice in chronic pain, subsequent to spinal nerve ligation (SNL) surgery. When administered subcutaneously to mice after SNL surgery, SR14150 but not SR16835 increased tail-flick latency, which was blocked by the opioid antagonist naloxone, but not by the 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). In contrast, both SR14150 and SR16835 had antiallodynic activity when mechanical allodynia was measured with von Frey monofilaments. This effect was completely blocked by SB-612111 but not by naloxone. On the other hand, morphine antinociception and antiallodynia were both blocked by naloxone and potentiated by SB-612111. These results indicate that, in mice, circuitry mediating antinociceptive activity in acute and chronic pain states is different. It is possible that during a chronic pain state, an up-regulated NOP system in the spinal cord leads to NOP receptor-mediated antiallodynia, which is blocked by NOP antagonists. However, supraspinal up-regulation could lead to an attenuation of morphine antinociception and antiallodynia, which can be alleviated by an NOP receptor antagonist. Thus, although neither NOP agonists nor antagonists are effective as analgesics in acute pain, they may have efficacy as analgesics, either alone or in combination with morphine, for treatment of chronic pain.
1-(1-环辛基哌啶-4-基)-吲哚啉-2-酮（SR14150）和 1-(1-(2,3,3a,4,5,6-六氢-1H-苯并[a]萘-1-基)哌啶-4-基)-吲哚啉-2-酮（SR16835）是中度选择性孤啡肽/孤啡肽 Q（NOP）受体激动剂。在体外的[（35）S]鸟苷 5'-O-（3-硫代三磷酸）测定中，SR14150 是 NOP 和 μ 阿片受体的部分激动剂，而 SR16835 是 NOP 受体的完全激动剂，对 μ 受体的效能较低。这些化合物在脊髓神经结扎（SNL）手术后的慢性疼痛小鼠中进行了抗伤害和抗感觉过敏活性测试。在 SNL 手术后，SR14150 而不是 SR16835 皮下给药可增加尾巴闪烁潜伏期，该潜伏期被阿片拮抗剂纳洛酮阻断，但不被 NOP 受体拮抗剂(-)-顺-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）阻断。相反，当使用 von Frey 单丝测量机械性感觉过敏时，SR14150 和 SR16835 均具有抗感觉过敏作用。这种作用完全被 SB-612111 阻断，但不受纳洛酮阻断。另一方面，吗啡的镇痛和抗感觉过敏作用均被纳洛酮阻断，被 SB-612111 增强。这些结果表明，在小鼠中，介导急性和慢性疼痛状态下镇痛作用的回路不同。在慢性疼痛状态下，脊髓中上调的 NOP 系统可能导致 NOP 受体介导的抗感觉过敏，该作用被 NOP 拮抗剂阻断。然而，脊髓上的上调可能导致吗啡镇痛和抗感觉过敏作用减弱，这可以被 NOP 受体拮抗剂缓解。因此，尽管 NOP 激动剂和拮抗剂在急性疼痛中均不是有效的镇痛药，但它们可能具有疗效，无论是单独使用还是与吗啡联合使用，都可用于治疗慢性疼痛。
