Intravenous Administration of Pyroglutamyl Apelin-13 Alleviates Murine Inflammatory Pain via the Kappa Opioid Receptor.

Shuangyu Lv,Yu Feng,Yuchen Zhou,Xinchun Wang,Xiaomei Zhang,Yanjie Yang,Binbin Cui

doi:10.3389/fnins.2020.00929

Abstract

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 Aplnr and Adcy2 gene expression in the prefrontal cortex, whereas Fos 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.

Highlights

Apelin, known as APLN, is the endogenous ligand for the apelin receptor (APJ, angiotensin II receptor-like 1), an orphan G protein-coupled receptor (GPCR) (Tatemoto et al, 1998)
This study demonstrated that i.v. or i.m. injection ofapelin13 or apelin-13 produced an antinociceptive effect in a murine formalin-induced paw inflammatory pain model
Our results demonstrate apelin13(F13A) to significantly block the antinociceptive effect of i.v.apelin-13 during the second phase of the mouse formalin test, suggesting the involvement of APJ in the antinociception induced by i.v. administration ofapelin-13

Summary

Introduction

Known as APLN, is the endogenous ligand for the apelin receptor (APJ, angiotensin II receptor-like 1), an orphan G protein-coupled receptor (GPCR) (Tatemoto et al, 1998). APJ, known as APLNR, was originally identified by O’Dowd et al (1993). The APJ receptor is composed of 380 amino acid residues, the sequence of which has considerable similarity to that. Pyroglutamyl Apelin-13 Alleviates Inflammatory Pain of the angiotensin II type 1 (AT1) receptor (54% for the transmembrane domains and 30% for the entire sequence). Angiotensin II does not bind to APJ (O’Dowd et al, 1993). The preproprotein of apelin (known as preproapelin) consists of 77 amino acids, coded by APLN which is located on chromosome Xq25–26.1 (Lee et al, 2000). A clinical study demonstrated that (pyr)apelin was to be the predominant cardiac isoform in patients with coronary artery disease (Maguire et al, 2009)

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