Lv Shuangyu, Zhang Xiaomei, Feng Yu, Zhou Yuchen, Cui Binbin, Yang Yanjie, Wang Xinchun
Institute of Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng, China.
Key Laboratory of Clinical Resources Translation, The First Affiliated Hospital of Henan University, Kaifeng, China.
Front Neurosci. 2020 Sep 8;14:929. doi: 10.3389/fnins.2020.00929. eCollection 2020.
Apelin is an endogenous neuropeptide, which has wide distribution in central nervous system and peripheral tissues. Pyroglutamyl apelin-13 [(pyr)apelin-13] is the major apelin isoform in human plasma. However, the role of peripheral (pyr)apelin-13 in pain regulation is unknown. The aim of this study was to investigate the effect of the peripheral injection of (pyr)apelin-13 on inflammatory pain using the formalin test as well as to evaluate the mechanistic basis for the effect. Results showed intravenous (i.v.) injection of (pyr)apelin-13 (10, 20 mg/kg) to significantly decrease licking/biting time during the second phase of the mouse formalin test. In contrast, i.v. injection of apelin-13 had no influence on such effect. Intramuscular injection of (pyr)apelin-13 reduced licking/biting time during the second phase only at a dose of 20 mg/kg. The antinociception of i.v. (pyr)apelin-13 was antagonized by the apelin receptor (APJ, angiotensin II receptor-like 1) antagonist, apelin-13(F13A). (pyr)apelin-13 (i.v. 20 mg/kg) markedly upregulated and gene expression in the prefrontal cortex, whereas gene expression was downregulated. The antinociception of i.v. (pyr)apelin-13 was blocked by the opioid receptor antagonist naloxone and the specific kappa opioid receptor (KOR) antagonist nor-binaltorphimine (nor-BNI). (pyr)Apelin-13 upregulated the dynorphin and KOR gene expression and protein levels in the mouse prefrontal cortex, not in striatum. (pyr)Apelin-13 did not influence the motor behavior. Our results demonstrate that i.v. injection of (pyr)apelin-13 induces antinociception via the KOR in the inflammatory pain mouse model.
Apelin是一种内源性神经肽，在中枢神经系统和外周组织中广泛分布。焦谷氨酸化Apelin-13[（焦谷）Apelin-13]是人类血浆中主要的Apelin亚型。然而，外周（焦谷）Apelin-13在疼痛调节中的作用尚不清楚。本研究的目的是使用福尔马林试验研究外周注射（焦谷）Apelin-13对炎性疼痛的影响，并评估其作用的机制基础。结果显示，静脉注射（焦谷）Apelin-13（10、20mg/kg）可显著减少小鼠福尔马林试验第二阶段的舔咬时间。相比之下，静脉注射Apelin-13对此效果无影响。肌肉注射（焦谷）Apelin-13仅在剂量为20mg/kg时可减少第二阶段的舔咬时间。静脉注射（焦谷）Apelin-13的镇痛作用被Apelin受体（APJ，血管紧张素II受体样1）拮抗剂Apelin-13（F13A）拮抗。（焦谷）Apelin-13（静脉注射20mg/kg）显著上调前额叶皮质中 和 基因的表达，而 基因表达下调。静脉注射（焦谷）Apelin-13的镇痛作用被阿片受体拮抗剂纳洛酮和特异性κ阿片受体（KOR）拮抗剂去甲二氢吗啡酮（nor-BNI）阻断。（焦谷）Apelin-13上调小鼠前额叶皮质而非纹状体中强啡肽和KOR基因的表达及蛋白水平。（焦谷）Apelin-13不影响运动行为。我们的结果表明，在炎性疼痛小鼠模型中，静脉注射（焦谷）Apelin-13通过KOR诱导镇痛作用。
