Dataset Information

In vitro determination of the efficacy of illicit synthetic cannabinoids at CB₁ receptors.

ABSTRACT: Background and purpose:The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB₁ receptors and is a major health concern. The properties of SCRA at CB₁ receptors are not well defined. Here we have developed an assay to determine acute CB₁ receptor efficacy using receptor depletion with the irreversible CB₁ receptor antagonist AM6544, with application of the Black and Leff operational model to calculate efficacy.

Experimental approach:Receptor depletion in mouse AtT-20 pituitary adenoma cells stably expressing human CB₁ receptors was achieved by pretreatment of cells with AM6544 (10 ?M, 60 min). The CB₁ receptor-mediated hyperpolarisation of AtT-20 cells was measured using fluorescence-based membrane potential dye. From data fit to the operational model, the efficacy (?) and affinity (K_A ) parameters were obtained for each drug.

Key results:AM6544 did not affect the potency or maximal effect of native somatostatin receptor-induced hyperpolarization. The ? value of ?⁹ -THC was 80-fold less than the reference CB receptor agonist CP55940 and 260-fold less than the highest efficacy SCRA, 5F-MDMB-PICA. The operational efficacy of SCRAs ranged from 233 (5F-MDMB-PICA) to 28 (AB-PINACA), with CP55940 in the middle of the efficacy rank order. There was no correlation between the ? and K_A values.

Conclusions and implications:All SCRAs tested showed substantially higher efficacy at CB₁ receptors than ?⁹ -THC, which may contribute to the adverse effects seen with these drugs but not ?⁹ -THC.

SUBMITTER: Sachdev S

PROVIDER: S-EPMC6965679 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

In vitro determination of the efficacy of illicit synthetic cannabinoids at CB1 receptors.

Sachdev Shivani S Vemuri Kiran K Banister Samuel D SD Longworth Mitchell M Kassiou Michael M Santiago Marina M Makriyannis Alexandros A Connor Mark M

British journal of pharmacology 20191210 24

<h4>Background and purpose</h4>The morbidity and mortality associated with recreational use of synthetic cannabinoid receptor agonists (SCRAs) may reflect strong activation of CB1 receptors and is a major health concern. The properties of SCRA at CB1 receptors are not well defined. Here we have developed an assay to determine acute CB1 receptor efficacy using receptor depletion with the irreversible CB1 receptor antagonist AM6544, with application of t ...[more]

PMID: 31412133

Similar Datasets

Project description:Neurolipids are a class of bioactive lipids that are produced locally through specific biosynthetic pathways in response to extracellular stimuli. Neurolipids are important endogenous regulators of neural cell proliferation, differentiation, oxidative stress, inflammation and apoptosis. Endocannabinoids (eCBs) and lysophosphatidic acid (LPA) are examples of this type of molecule and are involved in neuroprotection. The present study analyzes a possible relationship of the main receptor subtypes for both neurolipid systems that are present in the central nervous system, the CB1 and LPA1 receptors, by using brain slices from CB1 KO mice and LPA1-null mice. Receptor-mediated G protein activation and glycerophospholipid regulation of potential precursors of their endogenous neurotransmitters were measured by two different in vitro imaging techniques, functional autoradiography and imaging mass spectrometry (IMS), respectively. Possible crosstalk between CB1 and LPA1 receptors was identified in specific areas of the brain, such as the amygdala, where LPA1 receptor activity is upregulated in CB1 KO mice. More evidence of an interaction between both systems was that the CB1-mediated activity was clearly increased in the prefrontal cortex and cerebellum of LPA1-null mice. The eCB system was specifically over-activated in regions where LPA1 has an important signaling role during embryonic development. The modifications on phospholipids (PLs) observed in these genetically modified mice by using the IMS technique indicated the regulation of some of the PL precursors of both LPA and eCBs in specific brain areas. For example, phosphatidylcholine (PC) (36:1) was detected as a potential LPA precursor, and phosphatidylethanolamine (PE) (40:6) and PE (p18:0/22:6) as potential eCB precursors. The absence of the main cerebral receptors for LPA or eCB systems is able to induce modulation on the other at the levels of both signaling and synthesis of endogenous neurotransmitters, indicating adaptive responses between both systems during prenatal and/or postnatal development.

Dataset Information

In vitro determination of the efficacy of illicit synthetic cannabinoids at CB₁ receptors.

Publications

In vitro determination of the efficacy of illicit synthetic cannabinoids at CB<sub>1</sub> receptors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets