Abstract
Synthetic cannabinoid receptor agonists (SCRAs) are new psychoactive substances associated with acute intoxication and even death. However, the molecular mechanisms through which SCRAs may exert their toxic effects remain unclear—including the potential differential activation of G protein subtypes by cannabinoid receptor type 1 (CB1), a major target of SCRA. We measured CB1‐mediated activation of Gαs and Gαi/o proteins by SCRAs by examining stimulation (pertussis toxin, PTX treated) as well as inhibition (non‐PTX treated) of forskolin (FSK)‐induced cyclic adenosine monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably expressing CB1. Real‐time measurements of stimulation and inhibition of cAMP levels were made using a BRET biosensor. We found that the maximum concentration of SCRAs tested (10 µmol L−1), increased cAMP levels 12%‐45% above that produced by FSK alone, while the phytocannabinoid THC did not significantly alter cAMP levels in PTX‐treated HEK‐CB1 cells. All SCRAs had greater potency to inhibit FSK‐induced cAMP levels than to stimulate cAMP levels. The rank order of potencies for SCRA stimulation of cAMP (Gαs) was PB‐22 > 5F‐MDMB‐PICA > JWH‐018 ≈ AB‐FUBINACA > XLR‐11. By contrast, the potency of SCRAs for inhibition of cAMP (Gαi/o) was 5F‐MDMB‐PICA > AB‐FUBINACA > PB‐22 > JWH‐018 > XLR‐11. The different rank order of potency and EMax of the SCRAs to stimulate Gαs‐like signaling compared to Gαi/o signaling suggests differences in G protein preference between SCRAs. Understanding the apparent differences among these drugs may contribute to unravelling their complex effects in humans.
Highlights
The use of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) is associated with significant morbidity and mortality compared to use of ∆9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabis.[1,2] SCRAs are linked to a wide range of toxic effects including seizures, agitation, hypertension, cardiotoxicity, kidney damage, and sometimes death.[3,4] There has been a rapid increase in the number of structurally diverse SCRAs since 2010, with little known about their pharmacology and toxicology at time of identification.[5]
SCRAs are usually agonists at both cannabinoid type-1 and type-2 receptors (CB1 and CB2, respectively10); with the psychoactive effects attributed to the activation of cannabinoid receptor type 1 (CB1).11 We have previously described the in vitro quantitative measurement of SCRA efficacy at CB1, where all SCRAs tested showed between 20- and 300-fold greater agonist activity at CB1 compared to THC.[12]
This study examined whether SCRAs that are representative of structural classes confirmed in patients admitted to emergency departments with presumed SCRA toxicity stimulate Gαs-like cyclic adenosine monophosphate (cAMP) signaling via CB1
Summary
The use of synthetic cannabinoid receptor agonist (SCRA) new psychoactive substances (NPS) is associated with significant morbidity and mortality compared to use of ∆9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabis.[1,2] SCRAs are linked to a wide range of toxic effects including seizures, agitation, hypertension, cardiotoxicity, kidney damage, and sometimes death.[3,4] There has been a rapid increase in the number of structurally diverse SCRAs since 2010, with little known about their pharmacology and toxicology at time of identification.[5]. The mechanism(s) through which SCRAs exert different behavioral and physiological effects remains unclear, and which pathways modulated by CB1 activation mediate the specific pharmacological effects of SCRAs is unknown. While AB-CHIMINACA, previously identified as having a unique profile among SCRAs for elevating cAMP, appeared to signal, in part, through non-CB1 mechanisms
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