The Antitumor Peptide ERα17p Exerts Anti-Hyperalgesic and Anti-Inflammatory Actions Through GPER in Mice

Christophe Mallet,Catherine Coudert,Sylvain Lamoine,Yves Jacquot,Ludivine Boudieu,Alain Eschalier

doi:10.3389/fendo.2021.578250

Abstract

Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER). It is able to decrease the size of xenografted human breast tumors, in mice. As GPER has been reported to participate in pain and inflammation, we were interested in exploring the potential of ERα17p in this respect. We observed that the peptide promoted anti-hyperalgesic effects from 2.5 mg/kg in a chronic mice model of paw inflammation induced by the pro-inflammatory complete Freund’s adjuvant (CFA). This action was abrogated by the specific GPER antagonist G-15, leading to the conclusion that a GPER-dependent mechanism was involved. A systemic administration of a Cy5-labeled version of the peptide allowed its detection in both, the spinal cord and brain. However, ERα17p-induced anti-hyperalgesia was detected at the supraspinal level, exclusively. In the second part of the study, we have assessed the anti-inflammatory action of ERα17p in mice using a carrageenan-evoked hind-paw inflammation model. A systemic administration of ERα17p at a dose of 2.5 mg/kg was responsible for reduced paw swelling. Overall, our work strongly suggests that GPER inverse agonists, including ERα17p, could be used to control hyperalgesia and inflammation.

Highlights

Estrogens and their classical receptors, i.e. estrogen receptor a (ERa) and b, interfere with pain pathways, through specific proteins and different molecular mechanisms [1]
These results were confirmed by calculation of the area under the curve (AUC, in g.min.), where a significant difference was observed between ERa17p (2.5 and 10 mg/kg) or morphine (1 mg/kg, i.p., used as positive control) treated mice and vehicle-treated mice
Since we have previously demonstrated that the antiproliferative activity of ERa17p was mediated through the G protein-coupled estrogen receptor (GPER) [15], we have hypothesized that this membrane receptor could constitute the keystone of the anti-hyperalgesic action of the peptide

Summary

Introduction

Estrogens and their classical receptors, i.e. ERa and b, interfere with pain pathways, through specific proteins and different molecular mechanisms [1]. The newly discovered G protein-coupled estrogen receptor (GPER) is expressed, inter alia, in different regions of the central nervous system (CNS) such as the hippocampus and the hypothalamus, brain stem, the spinal cord, and autonomic and sensory ganglia [4,5,6,7], where it participates in a panel of neurophysiological events including pain. These effects are mediated through mechanisms involving an increase in the concentration of intracellular calcium and the accumulation of reactive oxygen species (ROS) [8,9,10]. GPER has an indisputable role in nociception via rapid steroid hormone signaling pathways

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