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Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling.

Authors :: Laprairie RB
Mohamed KA
Zagzoog A
Kelly MEM
Stevenson LA
Pertwee R
Denovan-Wright EM
Thakur GA
Source :: Frontiers in molecular neuroscience [Front Mol Neurosci] 2019 Oct 18; Vol. 12, pp. 257. Date of Electronic Publication: 2019 Oct 18 (Print Publication: 2019).
Publication Year :: 2019
Abstract: 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 [ <superscript>3</superscript> H]CP55940 to hCB1R and enhanced AEA-dependent [ <superscript>35</superscript> 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 and compounds designed to modulate both the prostaglandin and endocannabinoid systems.<br /> (Copyright © 2019 Laprairie, Mohamed, Zagzoog, Kelly, Stevenson, Pertwee, Denovan-Wright and Thakur.)