GPR171 Activation Modulates Nociceptor Functions, Alleviating Pathologic Pain.

Pyung Sun Cho,Ji Yeon Lim,Hyun Kim,Sun Wook Hwang,Young In Choi,Han Kyu Lee,Minseok Kim,Seung In Choi,Sung Jun Jung

doi:10.3390/biomedicines9030256

Pyung Sun Cho, Ji Yeon Lim + Show 7 more

Open Access

https://doi.org/10.3390/biomedicines9030256

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Journal: Biomedicines	Publication Date: Mar 5, 2021
Citations: 10	License type: CC BY 4.0

Affiliation: Korea University, Hanyang University

Abstract

Modulation of the function of somatosensory neurons is an important analgesic strategy, requiring the proposal of novel molecular targets. Many G-protein-coupled receptors (GPRs) have been deorphanized, but the receptor locations, outcomes due to their activations, and their signal transductions remain to be elucidated, regarding the somatosensory nociceptor function. Here we report that GPR171, expressed in a nociceptor subpopulation, attenuated pain signals via Gi/o-coupled modulation of the activities of nociceptive ion channels when activated by its newly found ligands. Administration of its natural peptide ligand and a synthetic chemical ligand alleviated nociceptor-mediated acute pain aggravations and also relieved pathologic pain at nanomolar and micromolar ranges. This study suggests that functional alteration of the nociceptor neurons by GPR171 signaling results in pain alleviation and indicates that GPR171 is a promising molecular target for peripheral pain modulation.

Highlights

We first examined GPR171 immunostaining in dorsal root ganglia (DRG), which initiate nociceptive signals
We found GPR171 expression in a subpopulation of DRG neurons (502 of 1498; 33.5%)
Peptidergic and non-peptidergic nociceptor markers including calcitonin gene-related peptide (CGRP) and isolectin B4 (IB4)-binding components were co-localized with GPR171 expression as well as the marker for myelinated DRG neurons, neurofilament 200 (NF200)

Summary

Introduction

Nociceptor neurons in the dorsal root ganglia (DRG) are in charge of the initiation of pain-related signals in the body [1]. G-protein-coupled receptors (GPRs) modulate the excitability of nociceptors, negatively or positively tuning the strength of the initiated signals. While some GPRs, such as prostaglandin EP2 and EP4 receptors and bradykinin B2 receptors strongly facilitate nociceptor excitation, other GPRs, including μ-opioid receptors, GABAB receptors, and chemokine-like receptor 1 receptors, reduce excitation, highly contributing to relieving pain [2,3,4,5,6]. Better understanding of the identities of pain-relieving GPRs and the molecular mechanisms underlying the reduction in excitability may help to contribute to the development of novel painkilling strategies

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