AUTHOR=Laprairie Robert B. , Mohamed Kawthar A. , Zagzoog Ayat , Kelly Melanie E. M. , Stevenson Lesley A. , Pertwee Roger , Denovan-Wright Eileen M. , Thakur Ganesh A. 

TITLE=Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=12

YEAR=2019

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2019.00257

DOI=10.3389/fnmol.2019.00257

ISSN=1662-5099

ABSTRACT=<p>In addition to its known actions as a non-selective cyclooxygenase (COX) 1 and 2 inhibitor, we hypothesized that indomethacin can act as an allosteric modulator of the type 1 cannabinoid receptor (CB1R) because of its shared structural features with the known allosteric modulators of CB1R. Indomethacin enhanced the binding of [<sup>3</sup>H]CP55940 to hCB1R and enhanced AEA-dependent [<sup>35</sup>S]GTPγS binding to hCB1R in Chinese hamster ovary (CHO) cell membranes. Indomethacin (1 μM) also enhanced CP55940-dependent βarrestin1 recruitment, cAMP inhibition, ERK1/2 and PLCβ3 phosphorylation in HEK293A cells expressing hCB1R, but not in cells expressing hCB2R. Finally, indomethacin enhanced the magnitude and duration of CP55940-induced hypolocomotion, immobility, hypothermia, and anti-nociception in C57BL/6J mice. Together, these data support the hypothesis that indomethacin acted as a positive allosteric modulator of hCB1R. The identification of structural and functional features shared amongst allosteric modulators of CB1R may lead to the development of novel compounds designed for greater CB1R or COX selectivity <italic>and</italic> compounds designed to modulate both the prostaglandin and endocannabinoid systems.</p>