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Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors

Marina Santiago, Shivani Sachdev, Jonathon C Arnold, Iain S McGregor, View ORCID ProfileMark Connor
doi: https://doi.org/10.1101/569079
Marina Santiago
1Department of Biomedical Sciences, Macquarie University, NSW, Australia
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Shivani Sachdev
1Department of Biomedical Sciences, Macquarie University, NSW, Australia
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Jonathon C Arnold
2The Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, NSW, Australia
3Discipline of Pharmacology, The University of Sydney, NSW, Australia
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Iain S McGregor
2The Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, NSW, Australia
4School of Psychology, The University of Sydney, NSW, Australia
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Mark Connor
1Department of Biomedical Sciences, Macquarie University, NSW, Australia
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Abstract

Introduction Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids, may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signalling. Therefore, we examined 6 common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signalling in vitro.

Materials and Methods Potassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real-time using FLIPR® membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 minutes. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels.

Results α-Pinene, β-pinene, β-caryophyllene, linalool, limonene and β-myrcene (up to 30-100 µM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10µM): (CB1: control, 59±7%; with terpenoids (10 µM each) 55±4%; CB2: Δ9-THC 16±5%, with terpenoids (10 µM each) 17±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signalling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 minutes the control hyperpolarization recovered by 63±6%, in the presence of the terpenoids recovery was 61±5%.

Discussion None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signalling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signalling pathways that do not involve potassium channels, however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioural effect of Cannabis.

Abbreviations
β-Car
β-caryophyllene
CBD
cannabidiol
HBSS
Hank’s balanced salt solution
RFU
relative fluorescence units
SEM
standard error of the mean
SST
somatostatin
Δ9-THC
Δ9-tetrahydrocannabinol
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 06, 2019.
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Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors
Marina Santiago, Shivani Sachdev, Jonathon C Arnold, Iain S McGregor, Mark Connor
bioRxiv 569079; doi: https://doi.org/10.1101/569079
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Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors
Marina Santiago, Shivani Sachdev, Jonathon C Arnold, Iain S McGregor, Mark Connor
bioRxiv 569079; doi: https://doi.org/10.1101/569079

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