Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

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

doi:10.3389/fnmol.2019.00257

Indomethacin Enhances Type 1 Cannabinoid Receptor Signaling

Front Mol Neurosci. 2019 Oct 18:12:257. doi: 10.3389/fnmol.2019.00257. eCollection 2019.

Authors

Robert B Laprairie^{1

2}, Kawthar A Mohamed¹, Ayat Zagzoog¹, Melanie E M Kelly^{2

3}, Lesley A Stevenson⁴, Roger Pertwee⁴, Eileen M Denovan-Wright², Ganesh A Thakur⁵

Affiliations

¹ College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada.
² Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
³ Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, NS, Canada.
⁴ School of Medical Sciences, The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
⁵ Center for Drug Discovery, Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA, United States.

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 [³H]CP55940 to hCB1R and enhanced AEA-dependent [³⁵S]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.

Keywords: allosteric modulator; cannabinoid; cannabinoid receptor; cell signaling; indomethacin; molecular pharmacology.