AUTHOR=Langedijk Jacqueline , Araya Erika Ivanna , Barroso Amanda Ribeiro , Tolenaars Dagmar , Nazaré Marc , Belabed Hassane , Schoene Jens , Chichorro Juliana Geremias , Oude Elferink Ronald 

TITLE=An LPAR5-antagonist that reduces nociception and increases pruriception

JOURNAL=Frontiers in Pain Research

VOLUME=3

YEAR=2022

URL=https://www.frontiersin.org/journals/pain-research/articles/10.3389/fpain.2022.963174

DOI=10.3389/fpain.2022.963174

ISSN=2673-561X

ABSTRACT=<sec><title>Introduction</title><p>The G-protein coupled receptor LPAR<sub>5</sub> plays a prominent role in LPA-mediated pain and itch signaling. In this study we focus on the LPAR<sub>5</sub>-antagonist compound 3 (cpd3) and its ability to affect pain and itch signaling, both <italic>in vitro</italic> and <italic>in vivo</italic>.</p></sec><sec><title>Methods</title><p>Nociceptive behavior in wild type mice was induced by formalin, carrageenan or prostaglandin E2 (PGE<sub>2</sub>) injection in the hind paw, and the effect of oral cpd3 administration was measured. Scratch activity was measured after oral administration of cpd3, in mice overexpressing phospholipase A2 (<inline-formula><mml:math id="M1" xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mrow><mml:mtext>sPLA</mml:mtext></mml:mrow><mml:mrow><mml:mn>2</mml:mn></mml:mrow><mml:mrow><mml:mtext>tg</mml:mtext></mml:mrow></mml:msubsup></mml:math></inline-formula>), in wild type mice (WT) and in TRPA1-deficient mice (<italic>Trpa1 KO</italic>). <italic>In vitro</italic> effects of cpd3 were assessed by measuring intracellular calcium release in HMC-1 and HEK-TRPA1 cells.</p></sec><sec><title>Results</title><p>As expected, nociceptive behavior (induced by formalin, carrageenan or PGE<sub>2</sub>) was reduced after treatment with cpd3. Unexpectedly, cpd3 induced scratch activity in mice. <italic>In vitro</italic> addition of cpd3 to HEK-TRPA1 cells induced an intracellular calcium wave that could be inhibited by the TRPA1-antagonist A-967079. In <italic>Trpa1 KO</italic> mice, however, the increase in scratch activity after cpd3 administration was not reduced.</p></sec><sec><title>Conclusions</title><p>Cpd3 has <italic>in vivo</italic> antinociceptive effects but induces scratch activity in mice, probably by activation of multiple pruriceptors, including TRPA1. These results urge screening of antinociceptive candidate drugs for activity with pruriceptors.</p></sec>