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首页> 美国卫生研究院文献>The Journal of Pharmacology and Experimental Therapeutics >Differential Effects of Nociceptin/Orphanin FQ (NOP) Receptor Agonists in Acute versus Chronic Pain: Studies with Bifunctional NOP/μ Receptor Agonists in the Sciatic Nerve Ligation Chronic Pain Model in Mice
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Differential Effects of Nociceptin/Orphanin FQ (NOP) Receptor Agonists in Acute versus Chronic Pain: Studies with Bifunctional NOP/μ Receptor Agonists in the Sciatic Nerve Ligation Chronic Pain Model in Mice

机译：Nociceptin / Orphanin FQ（NOP）受体激动剂在急性和慢性疼痛中的差异作用：坐骨神经结扎慢性疼痛模型中双功能NOP /μ受体激动剂的研究

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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 [35S]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.
机译：1-（1-环辛基哌啶-4-基）-吲哚-2-酮（SR14150）和1-（1-（2,3,3a，4,5,6-六氢-1H-苯-1-基）哌啶基-4-基）-吲哚啉-2-酮（SR16835）是中度选择性伤害感受器/孤啡肽FQ（NOP）受体激动剂。在体外[ 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，对μ受体的功效低。在脊髓神经结扎（SNL）手术后，使用处于慢性疼痛的小鼠测试了这些化合物的镇痛和抗痛觉过敏活性。在SNL手术后对小鼠皮下给药时，SR14150而不是SR16835会增加甩尾潜伏期，这被阿片类药物拮抗剂纳洛酮阻止，但未被NOP受体拮抗剂（-）-顺-1-甲基-7- [4阻断] -（（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）。相反，当用von Frey单丝测量机械异常性疼痛时，SR14150和SR16835都具有抗异常性疼痛活性。 SB-612111完全阻止了此作用，但纳洛酮并未完全阻止。另一方面，吗啡的抗伤害感受和抗异常性疼痛均被纳洛酮阻断，并被SB-612111增强。这些结果表明，在小鼠中，在急性和慢性疼痛状态下介导抗伤害感受活性的电路是不同的。在慢性疼痛状态下，脊髓中的NOP系统上调可能导致NOP受体介导的抗痛觉异常，这被NOP拮抗剂阻断。但是，脊髓上调可能导致吗啡抗伤害感受和抗异常性疼痛的减弱，这可以通过NOP受体拮抗剂来缓解。因此，尽管NOP激动剂和拮抗剂都不能作为急性疼痛的镇痛药，但它们可以单独或与吗啡组合作为镇痛药用于治疗慢性疼痛。

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