Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification

Maja Payrits,Zsuzsanna Helyes,Géza Makkai,Ádám Horváth,Éva Sághy,János Erostyák,Tünde Biró-Sütő,Miklós Kecskés,Éva Szőke,Angéla Kecskés,János Szolcsányi,Krisztina Pohóczky

doi:10.3390/ijms21145019

Maja Payrits, Zsuzsanna Helyes + Show 10 more

Open Access

https://doi.org/10.3390/ijms21145019

Copy DOI

Abstract

Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.

Highlights

The Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) cation channels are co-localized on capsaicin (CAPS)-sensitive polymodal nociceptors, and mediate pain and neurogenic inflammation [1,2,3,4]
We proved that pharmacological depletion of SMs, cholesterol or gangliosides diminished TRPV1 and TRPA1 channel activation both on transfected cells and native sensory neurons [31,32]
Peripheral and central administration of its low dose (0.01–10 ng) decreased acute, subacute, and persistent inflammatory pain in mouse models via TRPV1/TRPA1-independent mechanisms. This effect was suggested to be mediated by its specific G protein-coupled receptor (GPR) [47], which was later identified by direct binding of 3H-labeled Resolvin D2 (RvD2)

Summary

Introduction

The Transient Receptor Potential (TRP) Vanilloid 1 (TRPV1) and Ankyrin 1 (TRPA1) cation channels are co-localized on capsaicin (CAPS)-sensitive polymodal nociceptors, and mediate pain and neurogenic inflammation [1,2,3,4]. Sphingomyelinase hydrolyzes SM to phosphocholine and ceramide [37,38] It did act on the sensory neuronal cell bodies, and on the nerve terminals diminishing TRPV1 and TRPA1 activation-induced CGRP release, as a good indicator of channel inhibition [31]. Peripheral and central administration of its low dose (0.01–10 ng) decreased acute, subacute, and persistent inflammatory pain in mouse models via TRPV1/TRPA1-independent mechanisms This effect was suggested to be mediated by its specific G protein-coupled receptor (GPR) [47], which was later identified by direct binding of 3H-labeled RvD2. The present study investigated the effects of RvD1 and RvD2 on TRPV1 and TRPA1 receptor activation on trigeminal sensory neurons and peripheral sensory nerve endings and the involvement of lipid raft modification around tFhigeuseren1o.

Results

Primary Cultures of TG Neurons

Drugs and Chemicals

Statistical Analysis